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The affected member through whom a family with a genetic disorder is brought to attention



the person who brings the family to attention (can be affected or unaffected)


consanguineous matings

Couples who have >1 known ancestors in common r


Single-gene disorders

(also called Mendelian disorders) often present with characteristic and recognizable patterns in pedigrees. These are important patterns to recognize clinically



the observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait



the set of alleles that make up his or her genetic constitution (usually we are talking about a single locus)



a type of cell division in which diploid germ line cells give rise to haploid gametes. Prior to the initiation of meiosis, cells complete one round of DNA replication. The cells then undergo two successive rounds of chromosome segregation without an intervening round of DNA replication. Thus, the chromosome content is reduced from 4n to 2n in the first meiotic division, and from 2n to n in the second meiotic division, where n is the euploid number of chromosomes.


Two key differences between mitosis and meiosis

i) paternally- and maternally-derived homologous chromosomes pair at the onset of meiosis (prophase I), whereas the two homologs segregate independently in mitosis; and ii) reciprocal recombination events between maternal and paternal sister chromatids generate chiasmata (physical linkages) between homologs. In contrast, recombination between homologs is rare during mitosis.


Meiotic prophase I

Maternal and paternal homologs of each chromosome become paired or synapsed along their entire lengths, forming structures known as “bivalents”. This process requires the formation of a proteinaceous structure called the synaptonemal complex, which promotes inter-homolog interactions. Reciprocal recombination events occurring at this stage generate physical links between homologs. These attachments, or crossovers, are also known as chiasmata. On average, 2-3 crossovers occur on each chromosome, resulting in genetic reassortment between chromosomes. Importantly, the synaptonemal complex disassembles at the end of prophase I, and bivalents are therefore held together only by chiasmata.


first meiotic division

homologs are segregated to opposite poles of the cell. Meiosis I is the most error-prone step of the process, and chromosome nondisjunction at this stage is the most frequent mutational mechanism in humans.


Meiosis II

Unlike mitosis, chromosomes undergo a second round of segregation in meiosis II without an intervening round of DNA replication. Meiosis II is very much like a mitotic division.


Genetic consequences of meiosis

reduction in chromosome number from diploid to haploid, random segregation of homologous chromosomes, giving ~8x106 (or 223 ; 2 homologs for each of 23 chromosomes) different possibilities, random shuffling of genetic material due to crossover events, resulting in a vast increase in genetic variability from the above estimate



one round of chromosome segregation, resulting in daughter cells identical in chromosomal content to the parental cell, DNA replication precedes each round of chromosome segregation, no pairing of homologous chromosomes, infrequent recombination, centromeres on paired sister chromatids segregate at each anaphase, occurs in somatic cells and in germ line precursor cells prior to entry into meiosis



two rounds of chromosome segregation without an intervening round of DNA replication, parental cells must be diploid and the chromosome number is halved in the resultant cells, requires the pairing of homologous chromosomes and recombination for its successful completion, centromeres on paired sister chromatids divide only at anaphase II in a normal meiosis,occurs only in the germ line



the centromere is located in the middle of the chromosome, such that the two chromosome arms are approximately equal in length.



the centromere is slightly removed from the center.



the centromere is near one end of the chromosome. There are five in the human genome. In an acrocentric chromosome the p arm contains genetic material including repeated sequences such as nucleolar organizing regions, and can be translocated without significant harm, as in a balanced Robertsonian translocation. They also have distinctive masses of chromatin known as satellites attache dto their short arms by narrow stalks. These stalks contain hundresds of copies of genes encoding ribosomal rna and a variaty of repeptive sequences.



the centromere is at one end and only have a single arm. This does not occur in normal human karyotypes.



a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).


Short arm locations

p (petite)


long arm locative



chromosomal regions

Each chromosome is considered to be divided into different regions labeled p1, p2, p3; q1, q2, q3 etc., counting outwards from the centromere. Chromosomal regions are defined by specific landmarks (distinct morphological features) that include telomeres, centromeres, and banding patterns. Depending on the level of microscopic resolution, regions are subdivided into bands labeled p11 (pronounced “one-one”, not eleven!), p12, p13, and then p11.1 (p one-one point one), again counting outwards from the centromere. The centromere is designated “cen” and the telomere “tel”. It is conventional to refer to relative chromosomal locations in terms of proximity to the centromere. Thus, proximal 2q means the segment of the long arm of chromosome 2 that is closest to the centromere, and distal Xp means the portion of X most distant from the centromere, and therefore closest to the telomere.



Triploidy is a rare chromosomal abnormality. Fetuses with Triploidy, or Triploid Syndrome, have an extra set of chromosomes in their cells. One set of chromosomes has 23 chromosomes and is called a haploid set. Two sets, or 46 chromosomes, are called a diploid set. Three sets, or 69 chromosomes, are called a triploid set.



the situation in which an extra copy of an entire chromosome is present in the cell. There is variation among trisomies with regard to the parent and meiotic stage of origin of the additional chromosome. In general, however, maternal errors in the first meiotic division predominate among almost all trisomies. In addition, increasing maternal age, or more exactly, the proximity to menopause, is thought to be a significant risk factor for most, if not all, trisomies.



the condition in which a cell lacks one copy of a chromosome. Autosomal monosomies result in early embryonic lethality, although individuals that are monosomic for the X chromosome (45,X; Turner syndrome) survive. In contrast, most trisomies are compatible with at least some fetal development, but often result in spontaneous abortion.



the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg. Mosaicism can result from various mechanisms including chromosome non-disjunction, anaphase lag and endoreplication. Anaphase lagging appears to be the main process by which mosaicism arises in the preimplantation embryo. Mosaicism may also result from a mutation during development which is propagated to only a subset of the adult cells.


Marker chromosome

A small chromosome containing a centromere occasionally seen in tissue culture, often in a mosaic state (present in some cells but not in others). A marker chromosome may be of little clinical significance or, if it contains material from one or both arms of another chromosome, may create an imbalance for whatever genes are present; assessment to establish clinical significance, particularly if found in a fetal karyotype, is often difficult. They are usually in addition t normal chromosome complement and are called supernumerary chromosomes or extra structurally abnormal chromosomes. larger marker chromosomes invariably contain some material from one or both chromosome ars creating an imbalance for whatever genes are present. many marker chromosomes lack indentifiable telomeric sequences and are likely to be small ring chromosomes (are created when there are two breaks followed by a fusion)


Translocation, reciprocal

are usually an exchange of material between nonhomologous chromosomes.


Translocation, Robertsonian

a type of reciprocal translocation caused by breaks at or near the centromeres of two acrocentric chromosomes. The reciprocal exchange of parts gives rise to one large metacentric chromosome and one extremely small chromosome that may be lost from the organism with little effect because it contains so few genes. The resulting karyotype in humans leaves only 45 chromosomes, since two chromosomes have fused together.


causes of deletion

it may orginiate simply by chromosome breakage and loss of the acentric segment or from unequal crossing over between misaligned homologous chromosomes or sister chromatids. It can also occur from abnormal segregation of a balanced translocation of inversion


causes of duplications

can originate by unequal crossing over or by abnormal segragation from meiosis in a carrier of a translocation or inversion.


Terminal deletion

a deletion that occurs towards the end of a chromosome.


interstitial deletion

a deletion that occurs from the interior of a chromosome.



As a cell divides, during metaphase, the chromosomes all line up in the center of the cell. Microtubules attach to the chromosomes and pull them apart, so half the DNA ends up in each daughter cell. Before the DNA gets pulled apart, the chromosomes are free to recombine, so your chromosome 5, for example, is actually a mix of chromosome 5 from your mother and father. During recombination, the chromosomes must break and reattach. “Chromosomal breakpoints” refers to these places where they break. Occasionally something goes wrong and the reattachment happens in the wrong place…this can spell disaster. Usually the term “chromosomal breakpoints” is used in the context of some abnormality.



the number and appearance of chromosomes in the nucleus of a eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism. The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Normal karyotypes for females contain two X chromosomes and are denoted 46,XX; males have both an X and a Y chromosome denoted 46,XY. Any variation from the standard karyotype may lead to developmental abnormalities.



the condition in which cells contain an abnormal chromosome number. This condition is frequently the result of chromosome nondisjunction, the missegregation of chromosomes at metaphase in either mitosis or meiosis, such that daughter cells receive extra or fewer than the normal number of chromosomes. The most common mechanism is meiotic chromosome nondisjunction. Increased rates of meiosis I nondisjunction are associated with aberrations in the frequency or location, or both, of recombination events in meiosis I. Maternal age is also another contributing factor to aneuploidy.



the condition in which a cell lacks one copy of a chromosome


Down syndrome

(trisomy 21) is the most common human chromosomal disorder ascertained in liveborn infants (~1/900). In more than 95% of trisomy 21 cases, the additional chromosome 21 is maternal in origin, and dosage studies indicate that nondisjunction during maternal meiosis I is by far the most common cause.


Mechanism of nondisjunction

Meiotic recombination events (crossovers) are essential for tethering homologous chromosomes during the first meiotic division. Not surprisingly, disturbances in the recombination pathway are associated with abnormalities in chromosome segregation in the first meiotic division. Nondisjunction events are related to the positioning of chiasmata; crossover events that occur too near or too far from the centromere increase chromosome nondisjunction. Centromere-distal exchanges are less effective in ensuring appropriate spindle attachment and separation of paired homologs in meiosis I; centromere-proximal or excessive numbers of exchanges lead to entanglement of paired homologs in MI that then undergo reductional division leading to what appears to be MII errors. Nondisjunction events are also related to the frequency of crossover events. The reduction or absence of recombination events increases the likelihood of nondisjunction. Nondisjuction occurs more frequently in females


mitotic mutations

results in mesaicism as either somatic mutations, can also result in germ line mutations because germ line cells under go rounds of mitotic division before they undergo meiosis


meiotic mutations

result in germ line mutations


Meiotic Recombination

~2-3 cross-over events/pair of homologous chromosomes, Each cross-over, also called a chiasma, generates a physical link between homologues that is critical for normal chromosome disjunction (segregation). Cross-overs also occur within pseudoautosomal regions of sex chromosomes during male meiosis. recombination occurs between the two non sister chromosome. The cross over are the only thing holding together the homologues chromosome pairs. In XY complex there is a pseudohomologous region that holds together this region


synaptonemal complex

a highly ordered proteinaceous structure that assembles at the interface between aligned homologous chromosomes during meiotic prophase. The SC has been demonstrated to function both in stabilization of homolog pairing and in promoting the formation of interhomolog crossovers (COs).


Genetic variability

arises from recombination during meiotic prophase I and independent assortment of maternal and paternal chromosomes



are specialized chromosomal structures that hold the homologous chromosomes together until anaphase I. They are formed at sites where programmed DNA breaks generated by Spo11 undergo the full recombination pathway to generate crossovers. Only one chiasma per pair of homolog arms is needed to hold homologous chromosomes together during meiosis I.



maintained between sister chromatid arms during prophase of meiosis I


reductional division

The first cell division in meiosis, the process by which germ cells are formed. In reduction division, the chromosome number is reduced from diploid (46 chromosomes) to haploid (23 chromosomes). Also known as first meiotic division and first meiosis.


Nondisjuction during meiosis I

100% gamets have abnormalities. Increased rates of meiosis I nondisjunction are associated with aberrations in the frequency or location, or both, of recombination events in meiosis I.


Nondisjuction during meiosis II

50% of gametes have abnormalities



A diagrammatic representation of chromosome morphology characteristic of a species or a population.


g banding

completed using giemsa dye, higher AT bases= giemsa dark


Maternal Age Effect

The precise cause of the maternal age effect remains controversial. Two models are two- hit and terminilization



the heritable condition of possessing more than two complete sets of chromosomes. Polyploids arise when a rare mitotic or meiotic catastrophe, such as nondisjunction, causes the formation of gametes that have a complete set of duplicate chromosomes. Diploid gametes are frequently formed in this way. When a diploid gamete fuses with a haploid gamete, a triploid zygote forms, although these triploids are generally unstable and can often be sterile. it is believed that 10% of spontaneous abortions in humans are due to the formation of polyploid zygotes.


"two-hit” theory

suggests that several events may be responsible for increased aneuploidy in the eggs of women approaching menopause. The first “hit” is diminished recombination, caused either by a lack of chiasma or their mislocalization, resulting in a chromosome more susceptible to possible nondisjunction. The ability of oocytes to successfully complete chromosome segregation in the presence of unfavorable recombination events is thought to diminish over time, representing the second “hit” in this model.


terminalization theory

A second model suggests that the degradation of cohesin complexes over the course of the extended meiosis I arrest in oocytes results in precocious separation of homologs. In meiosis, the cohesin complex has dual functions: ensuring cohesion between sister chromatids and maintaining inter-homolog associations distal to the site of crossovers. Both activities are crucial in orchestrating the segregation of homologs at the first meiotic division. It is thought that there is little or no new deposition of the proteins of the cohesin complex during the extended meiosis I arrest in females. Therefore, the age-related degradation of cohesion established during fetal development has been postulated to allow “terminalization” to occur, the movement of chiasmata toward the ends of the homologs. Terminalization eventually leads to the premature separation of homologs and/or sister chromatins, resulting in aneuploidy.



The penetration of an ovum by two spermatozoa.



having a chromosome number that is four times the basic or haploid number.


Edwards syndrome

Trisomy 18, also called Edwards syndrome, is a chromosomal condition associated with abnormalities in many parts of the body. Individuals with trisomy 18 often have slow growth before birth (intrauterine growth retardation) and a low birth weight. Affected individuals may have heart defects and abnormalities of other organs that develop before birth. Other features of trisomy 18 include a small, abnormally shaped head; a small jaw and mouth; and clenched fists with overlapping fingers. Due to the presence of several life-threatening medical problems, many individuals with trisomy 18 die before birth or within their first month. Five to 10 percent of children with this condition live past their first year, and these children often have severe intellectual disability.


Patau syndrome

Trisomy 13, also called Patau syndrome, is a chromosomal condition associated with severe intellectual disability and physical abnormalities in many parts of the body. Individuals with trisomy 13 often have heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate), and weak muscle tone (hypotonia). Due to the presence of several life-threatening medical problems, many infants with trisomy 13 die within their first days or weeks of life. Only five percent to 10 percent of children with this condition live past their first year.


Klinefelter syndrome

Phenotypes include tall stature, hypogonadism, under-
developed secondary sexual characteristics, gynecomastia, usually infertile, some degree of language impairment. Incidence is 1/1000 live male births, half of cases result from errors in paternal meiosis I due to failure of recombination in pseudoautosomal regions. About 15% of cases result from mosaicism, and the most common mosaic karyotype is 46,XY/47,XXY


Turner syndrome

≥99% of 45, X fetuses abort spontaneously. Incidence is 1/4000 live female births,and most frequent karyotype is 45,X; 25% of individuals with Turner syndrome are mosaic. Phenotypes include short stature, webbed neck, edema of hands and feet, broad shield-like chest, renal and cardiovascular anomalies, and a failure in ovarian development.



the presence of at least two genetically different cells in a tissue that is derived from a single zygote. This condition results from mutations arising in single cells in either prenatal or postnatal life, generating clones of cells genetically different from the original zygote. The number of cells containing the mosiasim depends on how early in post-zygotic mitotic division. Human genomic instability occurs in cells dividing either meiotically or mitotically. Mutations that occur during mitotic cell cycles are passed on to daughter cells and distribute within organisms according to their timing and cellular phenotypes. Mosaic phenotypes are highly variable and the effects of mosaicism are very difficult to predict. effects on development vary with the timing of the nondisjunction event, the nature of the chromosomal abnormality, and the tissues affected. Types include polyploid and aneuploid mosaics Somatic chromosomal errors that occur during development lead to chromosomal mosaicism. Examples: 47,XX +21/46,XX (mosaic Down syndrome); 46, XX/46,XY (true hermaphroditism). Somatic chromosomal mutation is a common mechanism through which cell lines come to overexpress oncogenes or lose tumor suppressor genes. Mosaic parents with mild phenotypes can have fully affected offspring.


Germ line mosaicism

exists when a somatic mutation occurs early in development and generates a mutant sub-population of germ cells. Human female and male germ line cells undergo approximately 30 or 50 mitotic cell divisions, respectively, before differentiating into stem germ cells that then enter meiosis. A germ line mosaic individual is therefore capable of conceiving multiple offspring with apparent new (de novo) mutations. Thus, the recurrence risk for any genetic disorder is never “zero”. In addition, germ line mosaicism has been demonstrated in nearly every human Mendelian and chromosomal disorder and has important implications for genetic counseling.


Sex Chromosome Abnormalities

Aneuploidies are relatively common, and are more frequent than structural rearrangements. In general, the phenotypes associated with sex chromosome abnormalities are less severe than autosomal aneuploidies due to X chromosome inactivation and the relatively low number of genes that reside on the Y chromosome. Again, defects in sex chromosome number can often be traced to errors in maternal meiosis as a result of increased maternal age.



Holoprosencephaly is a disorder caused by the failure of the prosencephalon (the embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure and severe skull and facial defects. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. This can occur in patau syndrom



Having extra fingers or toes (6 or more) can occur on its own. There may not be any other symptoms or disease present. Polydactyly may be passed down in families. This trait involves only one gene that can cause several variations. Some genetic disease that can lead to this are rubinstein taybi syndrome and trisomy 13



an opening in the center of the abdominal wall where the umbilical cord meets the abdomen. Organs (typically the intestines, stomach, and liver) protrude through the opening into the umbilical cord and are covered by the same protective membrane that covers the umbilical cord. Edwards and Patau syndrome are associated with it



an increased tension of the muscles, meaning the muscle tone is abnormally rigid, hampering proper movement. Neonatal or congenital hypertonia, on the other hand, is usually a result of severe brain damage. Infants experiencing hypertonicity often have joint contractures and general discomfort as well as difficulty feeding.


47,XYY Syndrome

Indistinguishable physically or mentally from normal males and are usually fertile. Incidence is 1/1000 live male births, results from errors in paternal meiosis II, producing YY sperm. Increased risk of behavioral and educational problems, delayed speech and language skills. Not associated with criminality, as was originally hypothesized


Random variation

Random genomic variation is the fuel of evolution. Random variation in a highly ordered structure = almost always deleterious consequences. Genetic disease is the price we pay as a species to continue to have a genome that can evolve, i.e., that can adapt to new and changing environments


Findings from the first human genome sequence

The human genome is not static; it is dynamic and continues to evolve. There are ~30 new mutations occur in each individual. Shuffling of regions at each meiosis due to recombination. Can produce somatic DNA changes as well as germ-line DNA changes. There is no “one” human genome; there are many human genomes because of single nucleotide polymorphism (SNP). Average of 1 SNP every 1000 bp between any two randomly chosen human genomes. Genome is not organized in a random manner: Gene-rich regions/chromosomes (e.g. Chr 19), Gene-poor regions/chromosomes (e.g. Chr 13, 18, 21), Stable regions: majority of genome, Unstable, dynamic regions; many are disease-associated (e.g. SMA (Chr 5q13); DiGeorge syndrome (Chr 22q); 12 diseases (1q21)), GC-rich regions (38% of genome), AT-rich regions (54% of genome), Clustering (i.e. non-random distribution) of GC-rich and AT-rich regions is basis for chromosomal banding patterns (cytogenetics, karyotype analysis)


satellite DNAs

consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin. Some are in different parts of genome, e.g. used as the basis for cytogenetic banding. Some (a particular pentanucleotide sequence) are found as part of human-specific heterochromatic regions on the long arms of Chr 1, 9, 16 and Y (hotspots for human-specific evolutionary changes), “α-satellite” repeats (171 bp repeat unit) found near centromeric region of all human chromosomes; may be important to chromosome segregation in mitosis and meiosis.


Dispersed repetitive elements

Interspersed (or dispersed) DNA repeats (interspersed repetitive sequences) are copies of transposable elements interspersed throughout the genome.


The Alu family

The Alu family is a family of repetitive elements in the human genome. Modern Alu elements are about 300 base pairs long and are therefore classified as short interspersed elements (SINEs) among the class of repetitive DNA elements. The typical structure is 5'Part A- A5TACA6 -Part B - PolyA Tail - 3', where Part A and Part B are similar nucleotide sequences, but of opposite direction. Expressed another way, it is believed modern Alu elements emerged from a head to tail fusion of two distinct FAMs (fossil antique monomers) over 100 mkya, hence its dimeric structure of two similar, but distinct monomers (left and right arms, and in opposite directions) joined by an A-rich linker. The length of the polyA tail varies between Alu families. Alu elements are a common source of mutation in humans, but such mutations are often confined to non-coding regions where they have little discernible impact on the bearer.However, the variation generated can be used in studies of the movement and ancestry of human populations, and the mutagenic effect of Alu and retrotransposons in general has played a major role in the recent evolution of the human genome. There are also a number of cases where Alu insertions or deletions are associated with specific effects in humans, such as cancer and diabetes


Long Interspersed repetitive Elements

a group of non-LTR retrotransposons which are widespread in the genome of many eukaryotes. A typical L1 element is approximately 6,000 base pairs long and consists of two non-overlapping open reading frames (ORF) which are flanked by UTR and target side duplications. In the first human genome draft the fraction of LINE elements of the human genome was given as 21% and there war 300 bp related members and 500,000 copies in genome



also called transposons via RNA intermediates) are genetic elements that can amplify themselves in a genome and are ubiquitous components of the DNA of many eukaryotic organisms. They are one of the two subclasses of transposon, where the other is DNA transposon, which does not involve an RNA intermediate. They are particularly abundant in plants, where they are often a principal component of nuclear DNA.


Short Interspersed Elements

short DNA sequences (<500 bases) that represent reverse-transcribed RNA molecules originally transcribed by RNA polymerase III into tRNA, 5S ribosomal RNA, and other small nuclear RNAs. SINEs do not encode a functional reverse transcriptase protein and rely on other mobile elements for transposition. The most common SINEs in primates are called Alu sequences. Alu elements are approximately 350 base pairs long, do not contain any coding sequences, and can be recognized by the restriction enzyme AluI (hence the name).


Insertion-deletion polymorphisms (indels)

a molecular biology term for the insertion or the deletion of bases in the DNA of an organism. It has slightly different definitions between its use in evolutionary studies and its use in germ-line and somatic mutation studies. Types include Minisatellites and Microsatellites



a class of variable number tandem repeat (VNTR), is a section of DNA that consists of a short series of nucleobases (10–60 base pairs). Minisatellites, which are often simply referred to as VNTRs, occur at more than 1,000 locations in the human genome.



also known as simple sequence repeats (SSRs) or short tandem repeats (STRs), are repeating sequences of 2-5 base pairs of DNA. It is a type of Variable Number Tandem Repeat (VNTR). Microsatellites are typically co-dominant. They are used as molecular markers in STR analysis, for kinship, population and other studies. They can also be used for studies of gene duplication or deletion, marker assisted selection, and fingerprinting. They often contain di-, tri-, tetra-nucleotide repeats


Single Nucleotide Polymorphisms (SNPs)

a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes. The frequency is about 1 in ~1000 bp and are PCR-detectable markers, easy to score, widely distributed


Copy number variations (CNVs)

a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes. The variation in segments of genome can range from 200 bp – 2 Mb and can range from one additional copy to many. They can be array comparative genomic hybridization (array CGH). CNV loci may cover 12% of genome. Implicated in increasingly larger number of diseases. Some CNV regions involved in rapid & recent evolutionary change. Such regions are often enriched for human specific gene duplications, enriched for genome sequence gaps, enriched for recurrent human diseases. There is a link between evolutionarily adaptive copy number increases and increase in human disease (e.g. 1q21) They play a role of genome architecture


Comparative genomic hybridization

a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The aim of this technique is to quickly and efficiently compare two genomic DNA samples arising from two sources, which are most often closely related, because it is suspected that they contain differences in terms of either gains or losses of either whole chromosomes or subchromosomal regions (a portion of a whole chromosome). This is achieved through the use of competitive fluorescence in situ hybridization. In short, this involves the isolation of DNA from the two sources to be compared, most commonly a test and reference source, independent labelling of each DNA sample with a different fluorophores (fluorescent molecules) of different colours (usually red and green), denaturation of the DNA so that it is single stranded, and the hybridization of the two resultant samples in a 1:1 ratio to a normal metaphase spread of chromosomes, to which the labelled DNA samples will bind at their locus of origin. Using a fluorescence microscope and computer software, the differentially coloured fluorescent signals are then compared along the length of each chromosome for identification of chromosomal differences between the two sources.


Types of human DNA variation

Types include SNPs, indels, CNVs, and others: chromosomal or larger scale variations, rearrangements, translocations, etc. Variants can be silent (majority) or have a functional effect


gene family

a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions. Many human genes are members of gene families. Gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions. Gene families arise through gene duplication, a major mechanism underlying evolutionary change. Rationale: when a gene duplicates it frees up one copy to vary while the other copy continues to carry out a critical function. It facilitates innovation


Structural Variation

(also genomic structural variation) is the variation in structure of an organism's chromosome. It consists of many kinds of variation in the genome of one species, and usually includes microscopic and submicroscopic types, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. It is the b roadest sense: all changes in the genome not due to single base-pair substitutions: Copy number variations (CNVs) is the primary type of structural variation. They expose limitations of genome sequencing and genotyping platforms


limitations of genome sequencing

Nextgen DNA sequencing: No mammalian genome has been completely sequenced & assembled. Nextgen sequencing relies on short read sequences. Complex, highly duplicated regions are typically unexamined. Such regions are implicated in numerous diseases, e.g. 1q21. Genome-wide association studies (GWAS): “Missing heritability” for complex diseases: Many large-scale studies implicate loci (e.g. SNPs) that account for only a small fraction of the expected genetic contribution. Many regions of the genomes are unexamined by available “genome-wide” screening technologies: is this where the “missing heritability” lies?


genome-wide association study (GWA study)

an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases. These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays.


Structural chromosomal rearrangements

Chromosomal rearrangements require two DNA double strand breaks (DSBs) and can be induced by a variety of DNA damaging agents. Ionizing radiation directly induces breaks, but numerous other agents that damage DNA produce DSBs during repair. Because DSBs are necessary for meiotic recombination, rearrangements during meiosis are common. Duplications, deletions, inversions, insertions and translocations all appear to have breakpoints in chromosomal regions in which repeated sequences are prevalent. Nuclear protein complexes having both DNA repair and recombination activities share enzymes and associate with chromatin containing repetitive sequences. Structural rearrangements can be inherited and can also lead to further rearrangement during meiosis.Structural rearrangement can also occur with crossing over between repetitive DNA. Two basic types of structural rearrangements exist: balanced and unbalanced


balanced structural rearrangement

Individuals with balanced rearrangements have normal complements of chromosomal material, meaning there is no loss of genetic material. However, these rearrangements have varying stabilities during meiosis and mitosis. Examples of balanced structural rearrangements include the following: inversion, reciprocal translocation, and robertsonian translocation



occurs when one chromosome undergoes two double strand breaks of the DNA backbone and the intervening sequence is inverted prior to the rejoining of the broken ends. Paracentric inversions exclude the centromere. Pericentric inversions include the centromere. Chromosomes with inversions can have normal genetic complements, and therefore may produce no phenotypes in carriers of the rearrangement. However, inversions may generate abnormal gametes during meiosis. During the pairing of homologs in meiosis, a loop is introduced in the homolog containing the inversion, which maximizes the association of homologous sequences. If a crossover occurs within the inverted region of a paracentric inversion, both dicentric (two centromeres) chromosomes and acentric chromosomes can be generated, leading to chromosome breakage or loss. In pericentric inversions, crossovers within the inverted region can produce duplications and deletions.


robertsonian translocation

the fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (containing rDNA repeats). Robertsonian translocations result in the reduction of chromosome number, but are considered balanced rearrangements because the loss of some rDNA repeats is not deleterious. Carriers of Robertsonian translocations are phenotypically normal, but these rearrangements may lead to unbalanced karyotypes for their offspring, resulting in monosomies and trisomies. Robertsonian translocations involving chromosome 14 are by far the most frequent, constituting ~85% of all Robertsonian translocations. Common examples include a translocation involving chromosomes 14 and 21, karyotype 45,XX, or XY,der(14q;21q), and one involving chromosomes 14 and 13: 45,XY or XY,der(13q;14q). These individuals are trisomic 21 even though they only have 46 chromosomes. Note that some abbreviates a Robertsonian translocation as “rob”, but this is often simplified to “der” to indicate a chromosome derivative. There is no contribution with maternal age related to this mode of downs syndrome


reciprical translocation

results from the breakage and rejoining of non-homologous chromosomes, with a reciprocal exchange of the broken segments. As with inversions, carriers of reciprocal translocations have an increased risk of producing unbalanced gametes; balanced translocations are often found in couples that have had two or more spontaneous abortions, and also in infertile males. When the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis, a quadrivalent figure is formed. At anaphase, these chromosomes are segregated in one of three ways, referred to as alternate, adjacent-1, and adjacent-2 segregation.



a female with an inversion of the sequences between band 13 on the short arm and band 13 on the long arm of chromosome 9.



a female with a translocation involving chromosomes 9 and 22, which has been shown to cause chronic myelogenous leukemia.


alternate segregation

the most frequent meiotic segregation pattern, produces gametes that have either the normal chromosome complement or two reciprocal translocation chromosomes, both of which are balanced with respect to chromosome complement. Most likely normal. This mode of seperation is preferred over adjacent 1 and 2


adjacent-1 or 2 segregation

Results from pairing in meiosis 1 as quadrivalent complex. If you have 2 normal nonhomologous chrom A and B and their transloc forms a and b. During meosis, you get 1 off each nonhomologous in a cell (normal chrom+transl chrom Ab or aB). In adjacent 1, homologous cenromeres go to seperate daughter cells (as is normally the case in meiosis I), whereas in adjacent-2 (which is rare), homologous centromeres pass to the same daughter cell. segregation mechanisms lead to unbalanced gametes. The risks to offspring depend on the specific translocation in question, but the general empirical risk is 5-10% lethality. Division along one of the quadrivalent axis leads to 1, division along the other leads to 2. Such division leads to partial monosomy or trisomy.


Unbalanced structural rearrangement

the chromosome set has additional or missing material. Phenotypes of these individuals are likely to be abnormal. Duplication of genetic material in gametes can lead to partial trisomy after fertilization with a normal gamete, while deletions lead to partial monosomy. Examples of unbalanced chromosomal rearrangements include the following: deletion, duplication, ring chromosome, and isochromosome. If the resulting chromosomes don't have telomeres, centromeres, and origin of replication, then they will be lost from the population


deletion in chromosome

loss of genetic information that can arise by simple chromosome breakage (two dsDNA breaks) and rejoining, unequal crossing over between misaligned homologous chromosomes or sister chromatids, or by abnormal segregation of a balanced translocation or inversion. Includes terminal deletion and interstitial deletion. The clinical consequences of deletions reflect haploinsufficiency, where the contribution of the remaining normal allele is unable to prevent disease. Moreover, the severity of the phenotype depends on the size of the deletion and the number of genes affected.



a deletion of chromosome 5 in the region denoted p one-five. This deletion results in the Cri-du-chat syndrome.


Duplication of chromosome

gain of genetic information, which is generally less harmful than deletion, but can lead to abnormalities (i.e. partial trisomy 21). Duplications can also result from unequal crossing-over or by abnormal segregation during meiosis in a carrier of a translocation or inversion.


Ring Chromosome

a chromosome fragment that circularizes and acquires kinetochore activity for stable transmission to daughter cells (also called a marker chromosome).



the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart.



a male with a supernumary ring chromosome derived from the p11 to q34 region of chromosome 13.



a chromosome in which one arm is missing and the other duplicated in a mirror-image fashion, possibly occurring through an exchange involving one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere. The most common isochromosome observed is an isochromosome of the long arm of the X chromosome, karyotype i(Xq), but it also can occur on autosomes. A small percentage of Down syndrome patients have the 21q21q isochromosome e.g. 46,XX, i(21)(21q21q). Although this is a rare rearrangement, all the gametes of a phenotypically normal carrier of this isochromosome must contain either the 21q21q chromosome (giving 3 copies of chromosome 21 after fertilization), or gametes that lack chromosome 21, resulting in monosomy (inviability) upon fertilization. Thus, 100% of the viable offspring are abnormal.


causes of isochromosome formation

1)misdivision throught the centromerein meiosis II 2) more commonly, the exchange incolcing one arm of a chromosome and its homologue (or sister chromatid) in the region of the arm immediately adjacent to the centromere.


Recurrence risks of chromosomal restructuring

Most chromosome structural abnormalities found in fetuses and newborns that are associated with serious clinical effects are attributable to a random event. They are therefore unlikely to occur again. Moreover, a recurrence can be diagnosed in utero.


genetic counseling with chromosomal structural abnormalities

Occasionally a serious chromosomal abnormality can be inherited from a seemingly normal parent who carries a balanced chromosomal abnormality such as a translocation. In these comparatively rare cases, the recurrence risk could be much increased (e.g. isochromosome 21, where the recurrence risk is 100%!). It is necessary to examine the chromosomes of parents cytologically to exclude the possibility of an inherited abnormality, before counseling patients about recurrence risk.


Contiguous gene syndromes

a clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome. The combined phenotype of the patient is a combination of what is seen when any individual has disease causing mutations in any of the individual genes involved in the deletion. While it can be caused by deleted material on a chromosome, it is not, strictly speaking, the same entity as a segmental aneuploidy syndrome. A segmental aneuploidy syndrome is a subtype of CGS that regularly recur,usually due to non-allelic homologous recombination between low copy repeats in the region. Most CGS involve the X chromosome and affected male individuals


Wolf-Hirschhorn syndrome

a condition that affects many parts of the body. Almost everyone with this disorder has distinctive facial features, including a broad, flat nasal bridge and a high forehead. This combination is described as a "Greek warrior helmet" appearance. The eyes are widely spaced and may be protruding. The major features of this disorder include a characteristic facial appearance (facial clefting, prominent ears microcephaly), delayed growth and development, intellectual disability, and seizures. experience delayed growth and development. Intellectual disability ranges from mild to severe in people with Wolf-Hirschhorn syndrome. Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4. del(4p16.3)


Beckwith-Wiedemann syndrome

It is classified as an overgrowth syndrome, which means that affected infants are considerably larger than normal (macrosomia) and continue to grow and gain weight at an unusual rate during childhood. Many people with this condition are born with an opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel. Other abdominal wall defects, such as a soft out-pouching around the belly-button (an umbilical hernia), are also common. Most infants with Beckwith-Wiedemann syndrome have an abnormally large tongue (macroglossia), which may interfere with breathing, swallowing, and speaking. Other major features of this condition include abnormally large abdominal organs (visceromegaly), creases or pits in the skin near the ears, low blood sugar (hypoglycemia) in infancy, and kidney abnormalities.Children with Beckwith-Wiedemann syndrome are at an increased risk of developing several types of cancerous and noncancerous tumors, particularly a rare form of kidney cancer called Wilms tumor, a cancer of muscle tissue called rhabdomyosarcoma, and a form of liver cancer called hepatoblastoma. The condition usually results from the abnormal regulation of genes in a particular region of chromosome 11. Abnormalities involving genes on chromosome 11 that undergo genomic imprinting are responsible for most cases of Beckwith-Wiedemann syndrome. About 1 percent of all people with Beckwith-Wiedemann syndrome have a chromosomal abnormality such as a rearrangement (translocation) or abnormal copying (duplication) of genetic material from chromosome 11.


genomic imprinting

an epigenetic phenomenon by which certain genes can be expressed in a parent-of-origin-specific manner. Both maternal and paternal alleles of autosomal genes are typically expressed. However, approximately 100 autosomal genes in the mammalian genome are inherited in a silenced state from one of the two parents, and in a transcriptionally active state from the other, thereby rendering the individual functionally hemizygous for these genes. This process has been referred to as parental imprinting, genetic imprinting, or gametic imprinting, and represents an important epigenetic mechanism of inheritance. Imprinting takes place during gametogenesis, before fertilization. after concenption, the imprint controls gene expression within the imprinted region. It is reversible because a female must be able to convert her paternal inheriented allele in her germline so that she can pass of the maternal imprint to her offspring.


Cri du chat syndrome

del(5p15.2) also known as 5p- (5p minus) syndrome, is a chromosomal condition that results when a piece of chromosome 5 is missing. Infants with this condition often have a high-pitched cry that sounds like that of a cat. The disorder is characterized by intellectual disability and delayed development, small head size (microcephaly), low birth weight, and weak muscle tone (hypotonia) in infancy. Affected individuals also have distinctive facial features, including widely set eyes (hypertelorism), low-set ears, a small jaw, and a rounded face. Some children with cri-du-chat syndrome are born with a heart defect.


Angelman syndrome

del(15q11-q13) (maternal) Characteristic features of this condition include delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy) and a small head size (microcephaly). Delayed development becomes noticeable by the age of 6 to 12 months. Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. Hyperactivity, a short attention span, and a fascination with water are common. Most affected children also have difficulty sleeping and need less sleep than usual.The 15q11-q13 region contains three paternally expressed genes. Although no maternally expressed genes have so far been identified in this cluster, one is predicted to exist based on the fact that the inherited form of Angelman syndrome is exclusively inherited from mothers. These patients have a deletion of approximately the same region of chromosome 15 in prader willi syndrom, but on the maternally derived homolog. In this case, the information contained on the normal paternally derived chromosome 15 is inactivated due to DNA methylation. These defects effect the expression of UBE3A, which encodes a ubiquitin ligase involved in early brain development. 70% occur from deltion of maternal gene, followed by methylation of paternal alle. less than 5% occur from uniparental paternal disomy (nondisjuction is less common in males).


Williams syndrome

This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems. Williams syndrome is caused by the deletion of paternal genetic material from a specific region of chromosome 7. del(7q11.2), followed by methylation of the maternal copy (%70). 25% of cases result from uniparental disomy followed by methylation of both copies of the AS gene It is currently thought to arise due to defects in SNORD116 snoRNA genes (non-coding RNAs typically involved in guiding modifications of other RNAs). In PWS, these small nucleolar RNAs may be involved in mRNA modification, possibly by modulating alternative splicing. The region of this gene is flanked by multiple repetitive elements, therefore deletion in this region is common


Prader-Willi syndrome

In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes mellitus (the most common form of diabetes). People with Prader-Willi syndrome typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including temper outbursts, stubbornness, and compulsive behavior such as picking at the skin. Prader-Willi syndrome is caused by the loss of function of genes in a particular region of chromosome 15. In 70% of patients, the syndrome is the result of a cytogenetically observable deletion involving the long arm of chromosome 15 (15q11-q13), occurring on the chromosome 15 homolog inherited from the patient’s father. These patients have a normal, maternally derived homolog of chromosome 15. However, this region on the maternally derived chromosome is methylated, and transcriptionally silenced. del(15q11-q13)


Langer-Giedion syndrome

People with this condition have multiple noncancerous (benign) bone tumors called exostoses. Multiple exostoses may result in pain, limited range of joint movement, and pressure on nerves, blood vessels, the spinal cord, and tissues surrounding the exostoses. Affected individuals also have short stature and cone-shaped ends of the long bones (epiphyses). The characteristic appearance of individuals with Langer-Giedion syndrome includes sparse scalp hair, a rounded nose, a long flat area between the nose and the upper lip (philtrum), and a thin upper lip. Affected individuals may have some intellectual disability. It is caused by the deletion or mutation of at least two genes on chromosome 8. del(8q24.1) Also called Tricho-rhino-pharangeal syndrome


Miller-Dieker syndrome

a condition characterized by a pattern of abnormal brain development known as lissencephaly. Normally the exterior of the brain (cerebral cortex) is multi-layered with folds and grooves. People with lissencephaly have an abnormally smooth brain with fewer folds and grooves. These brain malformations cause severe intellectual disability, developmental delay, seizures, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties. Seizures usually begin before six months of age, and some occur from birth. They also tend to have distinctive facial features that include a prominent forehead; a sunken appearance in the middle of the face (midface hypoplasia); a small, upturned nose; low-set and abnormally shaped ears; a small jaw; and a thick upper lip. It is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17. del(17p13.3)


WAGR syndrome

Wilms tumor, aniridia (an absence of the colored part of the eye (the iris)), genitourinary anomalies, and mental retardation. WAGR syndrome is caused by a deletion of genetic material on the short (p) arm of chromosome 11. del(11p13)


DiGeorge syndrome

Medical problems commonly associated with DiGeorge syndrome include heart defects, poor immune system function, a cleft palate, complications related to low levels of calcium in the blood, and delayed development with behavioral and emotional problems. is a disorder caused by a defect in chromosome 22. del(22q11.2)


Velo-Cardio-Facial syndrome

characterized by medical problems include: cleft palate, or an opening in the roof of the mouth, and other differences in the palate; heart defects; problems fighting infection; low calcium levels; differences in the way the kidneys are formed or work; a characteristic facial appearance; learning problems; and speech and feeding problems. VCFS is also called the 22q11.2 deletion syndrome


Molecular Basis of Imprinting

Allele-specific methylation of CpG dinucleotides in the promoter regions of imprinted genes, established in one of the two germ lines and then maintained throughout embryogenesis, has been implicated in the maintenance of imprinting in somatic cells. However, there is some evidence that DNA methylation need not be placed within the transcriptional control regions of imprinted genes in order to affect the silencing of those genes. Also, recent investigations have revealed that in rare cases, DNA methylation is present in the expressed allele of imprinted genes, and is excluded from the silenced allele.


DNA methylation as a gene silencing mechanism

Hypermethylation may directly inhibit transcription either by repelling transcription factors (some DNA binding factors are known to be methylation-sensitive), or methylation may actively recruit factors that repress transcription. Mechanisms include selective interaction of MeCP2 with methylated DNA, ATP hydrolysis, Histone deacetylation and methylation, which result in compacted chromatin, hypoacetylated histones and transciptional repression. This methylation is transmitted to newly synthesized DNA by copying methylated regions of the template


DNA demethylation as a gene activation mechanism

The molecular basis of this activation is poorly understood, but a current model postulates that DNA methylation may prevent the binding of a transcriptional repressor.


Characteristics of imprinted genes.

These genes tend to be clustered together rather than spread throughout the entire genome. These clusters contain both maternally and paternally imprinted genes. The imprinted genes encode both proteins and non-coding RNAs.


Essential characteristics of the epigenetic mark.

The modification must be established in the gametes, the point in time when the maternal and paternal alleles of imprinted genes reside in separate cells and can be differentially modified. The allelic modification of imprinted genes must be stably maintained after fertilization. The modification must be capable of being erased and reset during the production of germ cells such that the appropriate sex-specific imprint is transmitted to the progeny. Wide scale erasure of all methylation marks during gametagenesis on all chromosome, followed by new imprinting in a gender specific manner


conversion of male and female imprinting

To accomplish such epigenetic inheritance, parental patterns of methylation, imprints, are erased in primordial germ cells as part of overall genomic reprogramming. New, sex-dependent imprints (patterns of methylation) are initiated during gametogenesis. Once sex-specific patterns of methylation are established during gametogenesis (by an unknown mechanism), the patterns are retained in somatic cells by maintenance methylation, which is responsible for methylating the newly synthesized daughter strand of DNA after replication.


DNA demethylation

reactivates gene expression, and erases the parental methylation patterns in developing gametes. Demethylation could result from the inhibition of the maintenance methyltransferase, DNMT1, or indirectly, through the inactivation of chromatin-remodeling proteins.


imprinting centers (IC)

Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind imprinter RNA transcripts (called BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis). Mutations at imprinting centers are heritable lesions that can generate the same abnormal phenotypes brought about by deletions or uniparental disomies involving imprinted loci.


Chromosomal Mutations of Imprinted Loci

Chromosomal mutations involving imprinted loci lead to parent of origin effects, meaning that the phenotype observed will depend upon which homolog (i.e. paternally derived or maternally derived) in the affected person’s genome has been deleted or duplicated. This phenomenon is illustrated in two contiguous gene syndromes called Prader-Willi and Angelman syndromes.


uniparental disomy

most commonly occurs when a trisomic conceptus (e.g. trisomy 15, maternal nondisjunction leading to two maternal, one paternal 15s) loses one of its extra chromosomes due to mitotic nondisjunction in early gestation. This chromosomal sorting error in effect “rescues” the developing pregnancy from spontaneous abortion but may result in an abnormal phenotype if both remaining homologs are derived from the same parent (e.g. reduction of the trisomy 15 genome above to the normal 46 chromosomal complement by loss of the paternally derived homolog. Since both remaining 15 homologs are maternal in origin, both carry maternally repressed loci. Normal development is dependent on expression of genes at the missing paternal 15q11-13 locus.


pericentric inversion

Inversions that include the centromere. Chromosomes with inversions may produce abnormal gametes. During meosis homologus regions align. With chromosomal inversions, a loop is produced to aligne homologous chromosomes. If crosing over occurs in the inverted sequences, duplication/ deletion will occur in the gametes. However, there seems to be mechanisms that repress crossing over in these regions so rates of abnormal chromosome gametes is low. the duplicated and deficient segments are the segments that are distal to the inversion.


paracenric inversions

these chromosomes also produce abnormal gametes but these gametes are not likely to produce live offspring because crossing over in these regions will produce dicentric or acentric chromosomes


Chronic myelogenous leukemia

95% of patients with cml have the philadelphia chromosome and an abnormal chromose 9 eg. 46,xx t(9;22)(q34;p11.2) the gene c-able is located at the break point on chromosome 9 and where it fuses is the BCR gene. This translocation creates the BCR-c-abl oncogene


robertsonian translocation carrier

In humans, when a Robertsonian translocation joins the long arm of chromosome 21 with the long arm of chromosome 14 (or 15), the heterozygous carrier is phenotypically normal because there are two copies of all major chromosome arms and hence two copies of all essential genes. However, the progeny of this carrier may inherit an unbalanced trisomy 21, causing Down Syndrome. A Robertsonian translocation in balanced form results in no excess or deficit of genetic material and causes no health difficulties. In unbalanced forms, Robertsonian translocations cause chromosomal deletions or addition and result in syndromes of multiple malformations, including trisomy 13 (Patau syndrome) and trisomy 21 (Down syndrome). Gametes can also be produced with monosomy, which is incompatabile with life


trisomy compatitble with life

Trisomy 18 (also called Edwards syndrome), Trisomy 13 (also called Patau syndrome), , and trisomy 21 (down syndrome). These occur due to fusion between acrocentric chromosomes. Monosomy is always incompatible with life


summary of mechanisms that lead to down syndrome

meiosis I nondisjunction (maternal) (95% of Down patients) (e.g. 47,XY,+21), Robertsonian translocation (4% of patients) (e.g. 46,XX,der(14;21)+21), Isochromosome (21q21q translocation) (e.g. 46,XY,i(21)+21), Mosaic Down syndrome- phenotype can be milder than typical trisomy 21, but patients exhibit wider variability in phenotypes due to variable portion of trisomy 21 cells in the embryo during development, Partial trisomy 21- very rare, has only a portion of chromosome 21 duplicated


non-allelic homologous recombination

a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles. aberrant recombination events lead to unbalanced chromosomal rearrangements. Two examples of diseases produced by this mechanism include charcot- marie tooth and hereditary neuropathy with liability to pressure palsies. Non-allelic homologous recombination (NAHR) between blocks of segmental duplication during meiosis leads to microdeletion and microduplication of the unique region bracketed by duplications.  If the region contains dosage-sensitive genes, disease may result.  If not, the duplicated chromosome is predisposed to additional rounds of microdeletion and duplication with increased probability



one of the most common inherited neurological disorders, affecting 1 in 2,500 people in the US, characterized by weakness of the foot and lower leg muscles, foot deformities known as hammertoes, and weakness and muscle atrophy of the hands late in the course of the disease, several forms of CMT exist; all affect the normal function of peripheral nerves, CMT type 1A is an autosomal dominant disorder caused by a duplication of 17p11.2, containing the gene for peripheral myelin protein-22 (PMP-22)


hereditary neuropathy with liability to pressure palsies

a slowly progressive, hereditary, neuromuscular disorder which makes an individual very susceptible to nerve injury from pressure, stretch or repetitive use. It is caused by deletion of PMP-22. Cytogenetic Location: 17p12 (same gene as in Charcot-Marie-Tooth)



mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence. Mechanisms include reversible, post-translational modifications of histones and DNA methylation are examples of epigenetic mechanisms that alter chromatin structure, thereby affecting gene expression.


Why is erasure and resetting of methylation patterns of imprinted genes during gametogenesis essential?

gametagenesis would result in embryos with no active compies or two active copies of imprinted genes would occur at high frequencies


parent of origin effect

occur when the phenotypic effect of an allele depends on whether it is inherited from the mother or the father. Several phenomena can cause parent-of-origin effects, but the best characterized is parent-of-origin-dependent gene expression associated with genomic imprinting.


Human Genome Structure

3 x 109 bp = haploid human genome sequence. Human genomic DNA is distributed on 46 nuclear chromosomes. 23 pairs of human chromosomes: 22 autosomes (1-22) and 1 pair of sex chromosomes (XX or XY). Each chromosome is believed to consist of a single, continuous DNA double helix. Chromosome number generally based on size: Chr 1: 245,203,898 bp and Chr 22: 49,476,972 bp


Linkage map

A linkage map is a genetic map of a species or experimental population that shows the position of its known genes or genetic markers relative to each other in terms of recombination frequency, rather than a specific physical distance along each chromosome. Linkage mapping is critical for identifying the location of genes that cause genetic diseases.


Human Genome Sequence

Human Genome is a record of human evolutionary history. Reflects results of different selection pressures that have occurred over evolutionary time and shaped our genome (and shaped us). Genes and genomic features that have been adaptive have been retained (many that were maladaptive were not retained). Genotype (genome) + environment = phenotype. Random variation is the fuel of evolution. Random variation in a highly ordered structure = almost always deleterious consequences. Genetic disease is the price we pay as a species to continue to have a genome that can evolve i.e. can adapt to changing environments


Characteristics of Human Genome

The human genome is not static; it is dynamic and continues to change and evolve. ~30 new mutations occur in each individual. Shuffling of regions at each meiosis due to recombination. Can produce somatic DNA changes as well as germ-line DNA changes e.g. cancer as a disease of “genome instability”. There is no “one” human genome; there are many (billions of different) human genomes: Single nucleotide polymorphism (SNP)- Average of 1 SNP every 1000 bp between any two randomly chosen unrelated human genomes. This means 99.9% identical and 3,000,000 differences


Human Genome Organization

Genome is not organized in a random manner. Gene-rich regions/chromosomes e.g. Chr 19. Gene-poor regions/chromosomes e.g. Chr 13, 18, 21 (viable trisomies). Stable regions: majority of genome. Unstable regions; many are disease-associated e.g. SMA (Chr 5q13); DiGeorge syndrome (Chr 22q); 12 diseases associated with unstable region on Chr 1 (1q21.1) GC-rich regions (38% of genome), AT-rich regions (54% of genome). Clustering (i.e. non-random distribution) of GC-rich and AT-rich regions is basis for chromosomal banding patterns (cytogenetics, karyotype analysis). This premise allows for G-banding (Giemsa staining).


human genome project goals

genetic map, physical map, DNA sequencing, gene identification, technology development, model organisms, informatics, ethical, legal and social issues, technology transfer, and public outreach


Human Genome Composition

~1.5% is translated (protein coding). 20-25% is represented by genes (exons, introns, flanking sequences involved in regulating gene expression). 50% “single copy” sequences. 40-50% classes of “repetitive DNA”- repeated hundreds to millions of times. Euchromatic regions (more relaxed) and heterochromatic regions (more condensed; more repeat-rich). Genome sequencing efforts focused on euchromatic regions. Heterochromatic regions essentially unsequenced. Many (>200) sequence gaps still remain even in euchromatic regions


duf1220 domain

a protein domain of unknown function that shows a striking human lineage-specific (HLS) increase in copy number and may be important to human brain evolution.[1] The copy number of DUF1220 domains increases generally as a function of a species evolutionary proximity to humans. DUF1220 copy number is highest in human (over 270, with some person-to-person variations).[2] and shows the largest HLS increase in copy number (an additional 160 copies) of any protein coding region in the human genome. For the above reasons and because DUF1220 sequences at 1q21.1 have undergone a dramatic and evolutionarily rapid increase in copy number in humans, a model has been developed that proposes that: 1) increasing DUF1220 domain dosage is the primary driving force behind the evolutionary expansion of the primate (and human) brain, 2) the instability of the 1q21.1 region has facilitated the rapid increase in DUF1220 copy number in humans, and 3) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human genome has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders. 1q21.1 dulications are linked to macrocephaly- autism and 1q21.1 deletions are linked to microcephaly- schizophrenia.


Implications of a highly dynamic genome

No human genome is completely sequenced and assembled. Some regions are either missed or are too complex and duplication-rich to assemble correctly with current methods. All regions of the genome do not look/behave the same way. Rapidly changing, complex genomic regions. Implicated in an increasing number of genetic diseases. Unexamined by available sequencing and genotyping platforms. Major current challenge for medical genetics. “Missing heritability” for many complex diseases. Large scale genome-wide association studies (GWAS) implicate loci that account for only a small % of expected genetic contribution


Mendelian Inheritance

Mendel found that there are alternative forms of factors—now called genes—that account for variations in inherited characteristics. For example, the gene for flower color in pea plants exists in two forms, one for purple and the other for white. The alternative versions of a gene are now called alleles. For each biological trait, an organism inherits two alleles, one from each parent. These alleles may be the same or different. An organism that has two identical alleles for a gene is said to be homozygous for that gene (and is called a homozygote). An organism that has two different alleles for a gene is said be heterozygous for that gene (and is called a heterozygote).



a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed (1) in males (who are necessarily homozygous for the gene mutation because they have only one X chromosome) and (2) in females who are homozygous for the gene mutation (i.e., they have a copy of the gene mutation on each of their two X chromosomes).



a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. It is determined by the proportion of individuals with a given genotype who also possess the associated phenotype. This differs from penetrance, which refers to the likelihood of the gene generating its associated phenotype at all. In contrast, expressivity refers to the influence of an expressed gene at the level of particular individuals. Expressivity can therefore be used to characterize qualitatively or quantitatively the extent of phenotypic variation within a particular genotype. The term is analogous to the severity of a condition in clinical medicine. this term is related to severity (the dimmer function)


autosomal dominant

A gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.


autosomal recessive

Describes a trait or disorder requiring the presence of two copies of a gene mutation at a particular locus in order to express observable phenotype; specifically refers to genes on one of the 22 pairs of autosomes (non-sex chromosomes)



the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. this is simply comparing the affected/ unaffected (on/off switch)



one gene influences multiple, seemingly unrelated phenotypic traits, an example being phenylketonuria, which is a human disease that affects multiple systems but is caused by one gene defect.[1] Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously. Pleiotropic gene action can limit the rate of multivariate evolution when natural selection, sexual selection or artificial selection on one trait favours one specific version of the gene (allele), while selection on other traits favors a different allele. The underlying mechanism of pleiotropy in most cases is the effect of a gene on metabolic pathways that contribute to different phenotypes. Genetic correlations and hence correlated responses to selection are most often caused by pleiotropy.


hardy-weinberg equilibrium

states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences. These influences include mate choice, mutation, selection, genetic drift, gene flow and meiotic drive. (p + q)2 = p2 + 2pq + q2 = 1.


Law of Segregation

During gamete formation, the alleles for each gene segregate from each other so that each gamete carries only one allele for each gene.


Law of Independent Assortment

Genes for different traits can segregate independently during the formation of gametes.


Law of Dominance

Some alleles are dominant while others are recessive; an organism with at least one dominant allele will display the effect of the dominant allele.


co dominant

occurs when the contributions of both alleles are visible in the phenotype. For example, in the ABO blood group system, chemical modifications to a glycoprotein (the H antigen) on the surfaces of blood cells are controlled by three alleles, two of which are co-dominant to each other (IA, IB) and dominant over the recessive i at the ABO locus.



Describes an individual who has only one member of a chromosome pair or chromosome segment rather than the usual two; refers in particular to X-linked genes in males who under usual circumstances have only one X chromosome


threats to mendelian inheritance

penetrance, age dependent penetrance, expressivity, sex influence and limitations, environmental factors, stochastic effects, modifier genes, phenocopies, pleiotropy


modifier genes

genes that have small quantitative effects on the level of expression of another gene


stochastic effects

Gene expression is a fundamentally stochastic process, with randomness in transcription and translation leading to significant cell-to-cell variations in mRNA and protein levels. These random effects that can influence the expression of phenotypes



when there is the same phenotyped (as a genetic condition) that is due to non-genetic factors


c banding

this is a cytological procedure that involves staining the centromeric region of each chromosome and constitutive herterochromatin


high resolution banding

this type of bading is achieved through either g or r banding to stain chromosomes that have been obtained in early stage of mitosis (prophase or prometaphase), when they are relatively uncondenced.






deletion, 46,XX,del(5p), Female with cri du chat syndrome due to deletion of part of short arm of one chromosome 5



derivative chromosome, der(1) Translocation chromosome derived from chromosome 1 and containing the centromere of chromosome 1



dicentric chromosome, dic(X;Y) Translocation chromosome containing centromeres from both the X and the Y chromosomes






fragile site, 46, Y fag(X)(q27.3) Male with fragile X chromosome



isochromosome, 46,X,i(Xq) Female with isochromosome fro the long arm of the X chromosome.






inversion, inv(3)(p25:q21) Pericentric inversion of chromosome 3



marker chromosome, 47,XX,+mar Female with an extra unidentified chromosome.



maternal origin, 47,XY,der(1)mat male with additional der(1) translocation chromosome inherited from his mother.



short arm of chromosome



paternal origin



long arm of chromosome



ring chromosome, 46,X,r(X) Female with ring X chromosome



reciprocal translocation



Robertsonian translocation



translocation, 46,XX,t(2;8)(q21;p13) Female with balanced translocation between chromosome 2 and chromosome 8, with breaks in 2q21 and 8p13



terminus, 46, X,Xq-(pter-->q21:) Female with partial deletion of the long arm from Xq21 to Xqter (nomenclature shows the portion of the chromosome that is present)



gain of, 47,XX,+21 Female with trisomy 21



loss of, 45,XX,-14,-21,+t(14q21q) Normal female carrier of a robertsonian translocation between the long arms of chromosomes 14 and 21; karyotype is missing a normal 14 and a normal 21



Chromosome 4 with a on of the short arm deleted,



break, 5qter -->5p15: deleted chromosome 5 in a patient with cri du chat syndrome, with a deletion breakpoint in band p15



break and join, 2pter-->2q21::8p13-->8pter Description of der(2) portion of t(2,8)



mosaicism, 46,XX/47,XX,+8 Female with two populations of cells, a normal karyotype and one with trisomy 8


results of nondisjunction

if the error occurs during meiosis I, the gamete with 24 chromosomes contains both the paternal and the maternal members of the pair. If it occurs during meiosis II, the gamete with the extra chromosome contains both copies of either the paternal or the maternal chromosome. a chromosome with too few or no recombinaitons or with rcombination too close to the centromere or telomere may be more susceptible to nondisjuction.



is a nonreciprocal type of translocation that occurs when a segment removed from one chromosome is inserted into a different chromosome either in its usual orientation or inverted. Because they require three chromosome breakks, insertions are rare. Can produce offspring with duplication or deletion of the inserted segment as well as normal offspring.


Epigenetic Characteristics

Epigenetic changes can lead to diversity of cell types. Different gene expression pattern/phenotype, identical genome. Inheritance through mitotic cell division, even through generations. This give stability to tissues. Like a Switch: ON/OFF, while the continuum of gene expression is regulated by transcription factors and DNA control elements. Erase-able (inter-convertible). Silencing of a tumor suppressor gene (TSG) by 5meC can lead to cancer. Histone deacetylases also silence genes.


DNA methylation

locks in the repressed state. DNA methylation occurs only on cytosines of CpG. Does not affect base paring of 5-meC with G. Contributes to gene silencing by solidifying the repressed state. Maintenance Methyltransferases Propagate Epigenetic Marks Through Somatic Cell Division


Histone H3

one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes. These modifications include the covalent attachment of methyl or acetyl groups to lysine and arginine amino acids and the phosphorylation of serine or threonine. Di- and Tri-methylation of Lysine 9 are associated with repression and heterochromatin, while mono-methylation of K4 is associated with active genes.


Examples of Epigenetic Phenomena

Chromatin-mediated gene silencing, eg. Heterochromatin domains, X-inactivation, Imprinting; Centromere marking by the histone variant CENP-A (attachment to spindle during mitosis); Prions (mad cow and Kreutzfeld-Jacob disease); Reinforcing feedback loops involving trans-acting factors that have a specific initiation event and are ‘inherited’ in the cytosol during cell division, Bacteriophage lambda repressor mechanism, Feedback loops in the initiation of certain cancers that operate through cytosolic signaling proteins and microRNAs.


epigenetic therapy

Correcting epigenetic patterns as a cancer therapy can Prevent inheritance of aberrant gene silencing. Cancer cells are known to have lots of methylation of tumor suppressor genes. Some cancer cells also have histone deacetylases to silence certain.


Prader-Willi Syndrome

Prader-Willi Syndrome results when genetic information is missing from the paternal allele of 15q11-q13. This region of chromosome 15 is imprinted, so that it is critical that information from both the maternal and paternal alleles are present for a person to be normal. PWS may result because of a deletion of the paternal allele, or because of uniparental disomy ( UPD - 2 copies present from one parent) of the maternal allele, or because of an imprinting error in how the alleles are marked, causing “virtual” maternal UPD. A deletion of the maternal allele causes a completely different disorder known as Angelman syndrome. There are other problems associated with chromosome 15q, including maternally inherited 15q interstitial duplication and isodicentric isochromosome 15q (IDIC 15). Many children with PWS are now treated with growth hormone which can significantly help control the obesity and improve short stature.


testing for prader willi syndrome

The maternal and paternal alleles are marked by different patterns of methylation. Therefore, methylation testing of this chromosome is one way to diagnose PWS or Angelman syndrome. If a deletion is present, a FISH test or a miccroarray can be done to confirm the diagnosis.


manifestation of PWS during infancy

Infants with PWS are very, very floppy (hypotonic). They have subtle but characteristic facial features (almond shaped eyes). Males often have undescended testicles. They have severe feeding problems which often necessitate placement of a feeding (Gtube) gastrostomy tube. Patients with PWS often have lighter pigmentation than their sibs and parents.


manifestation of PWS in toddlers

Usually between the ages of 2-4, the feeding problems completely reverse, and the child will eat anything and everything, without ever feeling sated. This feeding issue continues throughout life, and the patient may become very obese, unless treated with growth hormone.


Common Medical Issues in PWS

a number of medical issues are commonly seen in PWS patients including: Eyes: strabismus, nystagmus common, Orthopedics: scoliosis is common, Respiratory: obstructive sleep apnea may develop and is a contraindication to the use of growth hormone, Developmentally: mild-moderate cognitive disabilities are usually found, and behavioral issues are common.


Other Disorders Associated with Chromosome 15Q

 Abnormalities of 15q include Marker Chromosomes -Inverted duplication, Interstitial duplications, and Deletions (Angelman syndrome). Linkage disequilibrium between patients with Autism and polymorphisms in the GABAA –b3 locus on chromosome 15q have been reported. g-aminobutyric acid type-A is an important neurotransmitter in the CNS.


15q11-q13 chromosome anomalies

Maternally derived proximal 15q11-q13 chromosome anomalies are one of the most frequently reported cytogenetic abnormalities in patients with autism (related to GABAA receptor genes?). Supernumerary marker chromosomes (inverted duplicated isodicentric 15q, or IDIC 15). Phenotype: Autism, NOT dysmorphic, often hypotonic, seizures common


15q interstitial duplication

A piece of a chromosome can be copied, resulting in a duplication or partial Trisomy (in this picture, the duplication is an interstitial duplication in the middle of the chromosome. does not have a phenotype if it is inherited from the father, ONLY from the mother. Maternally derived interstitial 15q duplications. Phenotype: Autism, NOT dysmorphic, seizures common, hypotonia common during infancy (ie very similar to IDIC 15)


Angelman Syndrome

Etiology: 15q deletion in PWS/AS region from maternal allele, detected with FISH, UPD of 15q, or imprinting errors of 15q detected with methylation studies (the latter may have an association with conception via ART). Phenotype: mildly dysmorphic facial features which evolve with age, hypotonia in infancy progressing to spasticity in older patients, Intellectual Disability (ID), seizures, autism


Summary of chromosome abnormalities associated with chromosome 15

Prader-Willi Syndrome – (Paternal deletion). Angelman syndrome- (maternal deletion). IDIC 15 – associated with autism/hypotonia/Seizures/ID. Maternally inherited Interstitial duplication – associated with autism/ hypotonia/seizures/ID


Causes of Down Syndrome

Trisomy 21: 95% of patients with DS. Parents usually have normal chromosomes; recurrence risk is 1:100 + risk of maternal age. Unbalanced Translocation between chromosome 21 and another acrocentric chromosome: 3-4% of patients with DS. It is important to check karyotype of parents to see if they are carreers. Mosaic Tri 21(mixture of normal cells and cells containing Tri 21): 1-2 % of patients with DS. Phenotype tends to be more mild


Approach to Prenatal Counseling

Caused by an error of nondysjunction. Increasing risk with increasing maternal age. prenatal screening. 1st trimester screening – detection rate 82-87%. Ultrasound measurement of nuchal folds + blood markers: b-hCG (human chorionic gonadotropin) + PAPP-A (pregnancy-associated plasma protein A). 2nd trimester screening - detection rate 80%, quad screen - b-hCG (human chorionic gonadotropin), AFP (a-fetoprotein), unconjugated estriol, and inhibin level. Detection rate of 1st trimester + second trimester screening = 95%. Suspicion of DS based on 1st or second trimester screening can by confirmed by chromosome analysis via amniocentesis or CVS (chorionic villus sampling)


PAPP-A (pregnancy-associated plasma protein A)

This gene encodes a secreted metalloproteinase which cleaves insulin-like growth factor binding proteins (IGFBPs). It is thought to be involved in local proliferative processes such as wound healing and bone remodeling. Low plasma level of this protein has been suggested as a biochemical marker for pregnancies with aneuploid fetuses (fetuses with an abnormal number of chromosomes). For example, low PAPPA may be seen in prenatal screening for Down syndrome. Low levels may alternatively predict issues with the placenta, resulting in adverse complications such as intrauterine growth restriction, preeclampsia, placental abruption, premature birth, or fetal death.


b-hCG (human chorionic gonadotropin)

Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum during the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus. Due to its highly negative charge, hCG may repel the immune cells of the mother, protecting the fetus during the first trimester. It can be used second-trimester maternal serum screening for Down's syndrome


AFP (a-fetoprotein)

AFP is the most abundant plasma protein found in the human fetus. Plasma levels decrease rapidly after birth but begin decreasing prenatally starting at the end of the first trimester. Normal adult levels are usually achieved by the age of 8 to 12 months. AFP is measured in pregnant women through the analysis of maternal blood or amniotic fluid, as a screening test for a subset of developmental abnormalities.


unconjugated estriol

Estriol is only produced in significant amounts during pregnancy as it is made by the placenta. If levels of unconjugated estriol (uE3 or free estriol) are abnormally low in a pregnant woman, this may indicate chromosomal or congenital anomalies like Down syndrome or Edward's syndrome.


inhibin level

The inhibin A test is done to measure the amount of this hormone in a pregnant woman's blood to see if the baby may have Down syndrome. Inhibin A is made by the placenta during pregnancy.


Down Syndrome (Trisomy 21)

is the most common chromosomal abnormality seen in liveborn infants, with estimated incidence of 1/700 births. There are 3 kinds of trisomy which may be seen in liveborn infants: Trisomy 13, 18, and 21. The birth defects associated with Trisomies 13 and 18 are often life-threatening, and most babies with these diagnoses do not survive to see their 1st birthday. Each of these trisomies has their own unique appearance (phenotype) and associated anomalies. The diagnosis can be suspected at birth based on the baby’s physical exam.


Features of Infants with DS

Common physical features present at birth: Growth parameters are usually normal, midfacial hypoplasia, upslanting palpebral fissures*, epicanthal folds, small ears, large-appearing tongue, low muscle tone, increased joint mobility, short fingers, transverse palmar crease, Vth finger incurving (clinodactyly), increased space between toes 1 and 2



underdevelopment or incomplete development of a tissue or organ.


Caring for patients with DS

In addition to addressing routine well child care issues, there are many medical and developmental issues unique to DS which require screening, intervention and discussion. In order to best understand the updated recommendations for management of Common medical problems, Developmental/Neurological issues, Behavioral issues including autism (1/10)


Common medical issues

Cardiac issues are Seen in approximately 50% of patients with DS. All types of anomalies may be present, but Atrioventricular Canal is common to DS. Echocardiogram in the newborn period is recommended. Gastrointestinal occur in approx 10-15% of infants may have structural anomalies including Esophageal atresia, Duodenal atresia, and Hirschsprung’s. Many children with DS have functional GI issues including Feeding problems – very common, constipation - very common, GERD - very common, Celiac Dz (recommended screen is TTG + IgA). Ophthalmologic problems including blocked tear ducts, myopia, lazy eye, Nystagmus (often indicative of vision problems), and Cataracts (may present in the newborn period or develop during infancy; checking for a light reflex is important at every visit.) Ear, Nose and Throat Problems including chronic ear infections, Deafness (both sensorineural and conductive), chronic nasal congestion, enlarged tonsils and adenoids, and obstructive apnea (preschool age is a common time to present with this problem; it is also an issue in older children who develop obesity). Endocrin problems (autoimmune disorders) these problems include thyroid diseases (most commonly hypothyroidism which may by congenital or acquired), insulin dependent diabetes, alopecia areata, and reduced fertility (but normal puberty). Orthopedic Problems (hips, joint subluxation, atlantoaxial subluxation). Hematologic Issues (Myeloproliferative disorder in the newborn, increased risk of leukemia – 12-20x, Iron deficiency anemia). Developmental Issues (hypotonia effects gross motor development, Spectrum of intellectual disability – average is mild-moderate disabilities, speech problems- importance of sign language). Neurologic problems (hypotonia ranging from mild to severe and seizures, especially infantile spasms). Psychiatric Issues (depression, early Alzheimer’s, Autism – 1/10 patients with DS)


Transition to adult medical providers

Adult providers are not as good at coordinating services and communicating with specialists as pediatricians are – help your families to start taking ownership of this! When able, the patients themselves should learn what their main problems are, what medications they take, and what allergies they have. Teaching independence and self help skills is sometimes more important than academic skills. Appropriate social skills can be taught! Communication skills are key to success


Clinical cytogenetics

Clinical cytogenetics can detect common genetic disorders such as Down syndrome and provide the basis for understanding specific genetic aberrations in common human cancers, including whole chromosome gains, losses and inter-chromosomal translocations. The most recent addition to our diagnostic test menu is chromosomal microarrays (CMAs), a molecular test that identifies sub-microscopic genetic gains and losses. Cells are only looked at in mitosis, when the chromosomes are condensed


chromosomal microarrays (CMAs)

genetic testing technology primarily used to detect microdeletions and microduplications of genetic material. These changes are often grouped under the terminology "copy number variants" (CNVs). Everyone has some CNVs, which can be benign or disease-causing, inherited or new (de novo). Newer CMAs may also detect abnormalities such as uniparental disomy and evidence of consanguinity that can cause developmental abnormalities. The effects of CNVs on human health are largely unknown, but some have been implicated in developmental abnormalities including mental retardation, developmental delay, congenital birth defects, and autism. In the near future, specialized arrays will be used for the diagnosis of hematologic malignancies, replacing FISH studies for initial diagnoses. This technology looks at interphase DNA specifically


Cancer Cytogenetics

Chromosome analyses of bone marrow is performed to detect the common abnormalities associated with a diagnosis of leukemia or lymphoma. Specific chromosome abnormalities can also alert clinicians to the use of specific therapies. We will examine several examples, including: ALL, CML, and APML


acute lymphoblastic leukemia (ALL)

A common finding in childhood B-cell acute lymphoblastic leukemia (ALL) is high hyper-diploidy revealed by chromosome and FISH analyses. an acute form of leukemia, or cancer of the white blood cells, characterized by the overproduction of cancerous, immature white blood cells—known as lymphoblasts. In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells—such as red and white blood cells and platelets—in the bone marrow and by spreading (infiltrating) to other organs. ALL is most common in childhood with a peak incidence at 2–5 years of age, and another peak in old age. Cytogenetic analysis and molecular cytogenetic studies, such as fluorescence in situ hybridization (FISH), reveal recurring chromosome abnormalities in approximately 80 percent of ALL, including numerical and structural changes, such as translocations, inversions, or deletions. The t(9;22) is observed in about 2 to 5 percent of children compared with about 30 percent of adults. The t(12;21), which is detectable only by FISH or polymerase chain reaction (PCR) analysis, is observed in about 25 percent of children with B-lineage leukemia, compared with about 3 percent of adults.


chronic myelogenous leukemia (CML)

t(9;22) is diagnostic for chronic myelogenous leukemia (CML), which can be treated with tyrosine kinase inhibitors. a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. CML is now largely treated with targeted drugs called tyrosine kinase inhibitors (TKIs) which have led to dramatically improved long term survival rates since the introduction of the first such agent in 2001. In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. The fused BCR-ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division.


acute promyelocytic leukemia (APML)

t(15;17) is diagnostic for a specific acute promyeloid leukemia (APML), which can be treated with retinoid acid. Acute promyelocytic leukemia is a form of acute myeloid leukemia, a cancer of the blood-forming tissue (bone marrow). In normal bone marrow, hematopoietic stem cells produce red blood cells (erythrocytes) that carry oxygen, white blood cells (leukocytes) that protect the body from infection, and platelets (thrombocytes) that are involved in blood clotting. In acute promyelocytic leukemia, immature white blood cells called promyelocytes accumulate in the bone marrow. The overgrowth of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body, which causes many of the signs and symptoms of the condition. The mutation that causes acute promyelocytic leukemia involves two genes, the PML gene on chromosome 15 and the RARA gene on chromosome 17. A rearrangement of genetic material (translocation) between chromosomes 15 and 17, written as t(15;17), fuses part of the PML gene with part of the RARA gene. The protein produced from this fused gene is known as PML-RARα. This mutation is acquired during a person's lifetime and is present only in certain cells. This type of genetic change, called a somatic mutation, is not inherited. The PML-RARα protein functions differently than the protein products of the normal PML and RARA genes. The protein produced from the RARA gene, RARα, is involved in the regulation of gene transcription, which is the first step in protein production. Specifically, this protein helps control the transcription of certain genes important in the maturation (differentiation) of white blood cells beyond the promyelocyte stage. The protein produced from the PML gene acts as a tumor suppressor, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. The PML-RARα protein interferes with the normal function of both the PML and the RARα proteins. As a result, blood cells are stuck at the promyelocyte stage, and they proliferate abnormally. Excess promyelocytes accumulate in the bone marrow and normal white blood cells cannot form, leading to acute promyelocytic leukemia.


FISH (fluorescence in situ hybridization)

FISH probe panels are used for initial differential diagnosis, and as a means to monitor treatments or disease progression. The following is a short list of the fluorescence-labeled probes used for specific diseases, primarily hematologic malignancies, but also solid tumors (breast cancer, brain cancer, lung cancer, and selected sarcomas). Specific, cloned DNA sequences can enumerate number of specific chromosome or identify translocation. Probes are usually around 200bps. Some rearrangements are cryptic by standard cytogenetics and require FISH interpretation


SNP (single nucleotide polymorphism)-based CMA platform

a type of DNA microarray which is used to detect polymorphisms within a population. SNP chromosomal microarrays consist of synthetic DNA oligomers ‘spotted’ onto a ‘platform’ (usually a specially treated, microscope slide called a bead chip) using robotic technologies. An SNP array is a useful tool for studying slight variations between whole genomes. The most important applications of SNP arrays are for determining disease susceptibility and for measuring the efficacy of drug therapies designed specifically for individuals. Each individual has many SNPs. SNP-based genetic linkage analysis can be used to map disease loci, and determine disease susceptibility genes in individuals. The combination of SNP maps and high density SNP arrays allows SNPs to be used as markers for genetic diseases that have complex traits. For example, whole-genome genetic linkage analysis shows linkage for diseases such as rheumatoid arthritis, prostate cancer, and neonatal diabetes. This information can help design drugs that act on a group of individuals who share a common allele - or even a single individual. A SNP array can also be used to generate a virtual karyotype using software to determine the copy number of each SNP on the array and then align the SNPs in chromosomal order. SNPs can also be used to study genetic abnormalities in cancer. For example, SNP arrays can be used to study loss of heterozygosity (LOH). LOH occurs when one allele of a gene is mutated in a deleterious way and the normally-functioning allele is lost. LOH occurs commonly in oncogenesis. For example, tumor suppressor genes help keep cancer from developing. If a person has one mutated and dysfunctional copy of a tumor suppressor gene and his second, functional copy of the gene gets damaged, they may become more likely to develop cancer.


The three mandatory components of the SNP arrays are:

1. The array that contains immobilized nucleic acid sequences of target. 2. One or more labeled allele-specific oligonucleotide (ASO) probes. 3. A detection system that records and interprets the hybridization signal.


CMA Methods

Sample—usually peripheral blood--DNA is amplified and labeled. After post hybridization washes, the arrays are viewed via an optical scanner, and a statistical test is performed for all the spots/color intensities for each probe, comparing to a population of 50 normal individuals’ DNA. The SNP platform provides information on intensity and on runs of homozygosity, possibly revealing autosomal recessive conditions. Thus, the whole genome can be investigated simultaneously—like performing thousands of FISH tests! CMA testing frequently reveals duplications or deletions of genetic material that cannot be seen by standard cytogenetics and light microscopy.


Copy number variants [CNVs]

An important consideration is that all human populations contain multiple genomic variants—that is duplications or deletions within the DNA for which there is no phenotypic consequence. These cannot be detected at the chromosome level. An important resource exists that has banked known genomic variants in the normal human population. This resource contains published literature as well as the precise mapping of the variants and known disease regions. There are over 35,000 definitive CNVs in our human population, and these are known to be heritable. Each normal individual carries ~10-20 CNVs. The size of the copy number variant may be 100’s of kilobases to megabase-pairs of genomic DNA.


laboratory test algorithms for children with developmental delays

Test protocol (algorithm) for diagnosing infants, children, or adults with autism, cognitive disability, developmental delays, failure to thrive, dysmorphic features, seizures, and/or other multiple congenital anomalies (i.e. heart abnormalities): 1. If deletion or duplication is detected by CMA consult DGV. 2. Parental FISH studies will be offered to determine if this finding is a rare, normal, familial variant. 4. If a deletion or duplication is found in one or both parents, other family members may be tested by FISH. Often extensive consultation between the clinical geneticist, genetic counselors and cytogeneticist are required. 5. If the deletion or duplication is not found in either parent, and it is not found in the genomic variants Database, further data-base mining, literature searches are performed. Often a gene or genes mapped in the region of deletion or duplication reveals a syndromic association.


waddington's landscape as an epigenetic visualization

Waddington's epigenetic landscape is a metaphor for how gene regulation modulates development. One is asked to imagine a number of marbles rolling down a hill towards a wall. The marbles will compete for the grooves on the slope, and come to rest at the lowest points. These points represent the eventual cell fates, that is, tissue types. Waddington coined the term chreode to represent this cellular developmental process. This idea was actually based on experiment: Waddington found that one effect of mutation (which could modulate the epigenetic landscape) was to affect how cells differentiated. He also showed how mutation could affect the landscape and used this metaphor in his discussions on evolution—he was the first person to emphasise that evolution mainly occurred through mutations that affected developmental anatomy.


Inheritance of a Chromatin State

During DNA replication, newly made histones are recurited onto the new strand. Problem for maintaining an epigenetic state (DNA methylation or histone mod.): DNA is half old/half new and therefore histones are half old/half new. Therefore new nucleosoe assembly takes place and the modifications are reestablished.


low hypodiploidy in cancer cells

poor prognosis, because loss of tumor suppressor cells. the chromosome mutation of leukemic cells with 45 chromosomes or less. It has been determined that the prognosis of hypodiploid is much less than standard acute lymphoblastic leukemia. The lower the chromosome count, the lower the survival rate.


high hyperdiploidy in cancer cells

near trisomy, good prognosis,


Acute promyeloid leukaemia (APML)

APML is most commonly associated with a swapping over (translocation) of chromosomes 15 and 17. This causes parts of a gene from each of these chromosomes to "join" and create a fusion gene called PML/RARA. In some cases, other chromosomes may translocate and cause a variant APML, but this is quite rare. In APML, promyelocytes (an immature type of White Blood Cell) accumulate in the bone marrow, causing a decreased number of normal white blood cells in the blood and reduces production of other types of cells like red blood cells and platelets. All Trans Retinoic Acid (ATRA) is a medication given for the treatment of APML (for those who have the PML-RARA fusion gene present in their APML) and is commenced as soon as the diagnosis is suspected. It is not a chemotherapy agent, but works by overcoming the immature promyelocyte cells' inability to absorb retinoic acid (a compound required for cell growth and development). ATRA enables these promyelocytes to develop and then die as would normally happen.


auer rod

clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts. They can be seen in the leukemic blasts of acute myeloid leukemia with maturation and acute promyelocytic leukemia (known as acute myeloid leukemia M2 and M3, in the FAB classification, respectively) and in high grade myelodysplastic syndromes and myeloproliferative syndromes. They are composed of fused lysosomes/primary neutrophilic granules and contain peroxidase, lysosomal enzymes, and large crystalline inclusions. Morphologically, the Auer "rods" come in all sizes and shapes. They have been described as needle-shapes with pointed ends (most common), comma-shapes, and diamond-shapes; others were long and rectangular. Occasional corkscrew forms and rare granular Auer bodies were also noted. More appropriately, they can be referred to as Auer bodies.


Chronic myelogenous (or myeloid or myelocytic) leukemia (CML)

a cancer of the white blood cells. CML was the first cancer to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr-abl fusion gene product is also a tyrosine kinase. The fused BCR-ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. Gleevec can treat this



tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). In order to survive, cells need signaling through proteins (signal cascade) to keep them alive. Some of the proteins in this cascade use a phosphate group as an "on" switch. This phosphate group is added by a tyrosine kinase enzyme. In healthy cells, these tyrosine kinase enzymes are turned on and off as needed. In Ph-positive CML cells, one tyrosine kinase enzyme, BCR-Abl, is stuck on the "on" position, and keeps adding phosphate groups. Imatinib blocks this BCR-Abl enzyme, and stops it from adding phosphate groups. As a result, these cells stop growing, and even die by a process of cell death (apoptosis). Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug's action.


Down syndrome predisposition to cancer

DS infants and children have 20-100 fold. Elevated risk for developing ALL or AML. 500 x more likely to get AMKL (Acute Megakaryo-Blastic leukemia)


AMKL (Acute Megakaryo-Blastic leukemia)

a form of leukemia where a majority of the blasts are megakaryoblastic. This category of AML is associate with 30% or more blasts in the marrow, blast are identified as being of megakaryocyte lineage by expression of megakaryocyte specific antigens and platelet peroxidase reaction on electron microscopy. It is associated with GATA1, and risks are increased in individuals with Down syndrome. However, not all cases are associated with Down syndrome, and other genes can also be associated with AMKL. Another related gene is MKL1, which is also known as "MAL". This gene is a cofactor of serum response factor.



an acute form of leukemia, or cancer of the white blood cells, characterized by the overproduction of cancerous, immature white blood cells—known as lymphoblasts. In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells—such as red and white blood cells and platelets—in the bone marrow and by spreading (infiltrating) to other organs. ALL is most common in childhood with a peak incidence at 2–5 years of age, and another peak in old age. cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes) cells are the problem.


Advantages of Chromosomal Microarray

Detects chromosomal gains and losses, some of which may be “submicroscopic”; one array = 850,000 FISH studies! Intensity and allelic imbalance. Detects abnormalities in known “hot spots” (areas of known genetic disease - 22q11.2 deletion syndrome, 3,200 others). Genome-wide arrays may also detect abnormalities in “backbone” of genome, Can also be used to characterize chromosome abnormalities detected by karyotyping. Specific size of imbalance and genes involved


Limitations of CMA

Cannot detect balanced rearrangements, i.e. Balanced translocations, inversions. Cannot detect specific genetic/DNA mutations, single base pair changes, e.g., Cystic Fibrosis. May not detect low-level mosaicism (<20%). Detection of copy number variants (CNVs) may have unclear clinical significance


Detection of CNVs

Defined as regions of the genome that occur in varying copy numbers in the normal population. Generally thought to be benign, but can also include genes that may lead to disease susceptibility. May need to test parents (usually FISH) to determine if inherited: familial variant. May have unclear significance, making genetic counseling challenging


Pathogenic vs. Benign CNVs

Region(s) of known clinical significance: Known del/dup or Mendelian disorders. Comparison with other cases in literature, databases. Gene Content: Dependent upon size and location. May be inherited or de novo. If found in parent, likely familial variant



A CNV is defined as a DNA segment longer than 1 kb with a variable copy number compared with a reference genome. Because array-based aneuploidy profiling measures differences in fluorescence intensities after hybridization to an array of bacterial artificial chromosomes or oligonucleotide probes of a patient DNA sample in comparison with a reference sample, these assays actually measure DNA copy number changes (CNCs). “Variants” are generally being considered as alterations or uncommon forms of no clinical significance. To account for this, and to avoid confusion, the term CNC, rather than CNV has been proposed. Detection of significant numbers of CNCs in healthy individuals has presented us with the challenge of distinguishing phenotypically neutral CNCs from those contributing to the patient's phenotype.


CMA Reports

Determine size and location of deletions/duplications (most > 200 Kbp) = leads to further investigation in data bases. & are supported by multiple levels of SNP data. Genomic Content of these Regions: Copy number variants: common CNV’s not reported, Genes/functions & discussion of known phenotypes. Is this de novo or inherited? CMA cannot detect very low level mosaicism, heterodisomy, or balanced chromosome rearrangements. Genomic Content of these Regions: Copy number variants: common CNV’s not reported, Genes/functions & discussion of known phenotypes


snrpn gene

The protein encoded by this gene is one polypeptide of a small nuclear ribonucleoprotein complex and belongs to the snRNP SMB/SMN family. The protein plays a role in pre-mRNA processing, possibly tissue-specific alternative splicing events. Although individual snRNPs are believed to recognize specific nucleic acid sequences through RNA-RNA base pairing, the specific role of this family member is unknown. The protein arises from a bicistronic transcript that also encodes a protein identified as the SNRPN upstream reading frame (SNURF). Multiple transcription initiation sites have been identified and extensive alternative splicing occurs in the 5' untranslated region. Additional splice variants have been described but sequences for the complete transcripts have not been determined. The 5' UTR of this gene has been identified as an imprinting center. Alternative splicing or deletion caused by a translocation event in this paternally-expressed region is responsible for Prader-Willi syndrome and Angelman syndrome due to parental imprint switch failure. SNRPN-methylation is used to detect uniparental disomy of chromosome 15.[3] After fluorescent-in-situ-hybridization has confirmed the presence of either SNRPN or UBE3A (a neighboring gene that is also imprinted), the methylation test (of SNRPN) can reveal whether the patient has uniparental disomy. SNRPN is maternally methylated (silenced). UBE3A appears to be paternally methylated (silenced)


chromosome 15

it is imprinted. Paternal deletion= PWS. Maternal deletion= angleman syndrome. Unipartenal disomy can also lead to these diseases (two maternal= PWS). The mythelation patterens are different depending on whether it is inherited from mother or father. It is also possible to have an interstitial duplication or an isodicentric isochromosome (marker chromosome).



also known as heterotropia or colloquially as crossed eyes, is a condition in which the eyes are not properly aligned with each other. The extraocular muscles control the position of the eyes. Thus, a problem with the muscles or the nerves controlling them can cause paralytic strabismus. The muscles are controlled by cranial nerves III, IV, or VI. An impairment of cranial nerve III causes the associated eye to deviate down and out and may or may not affect the size of the pupil. Impairment of cranial nerve IV, which can be congenital, causes the eye to drift up and perhaps slightly inward. Sixth nerve palsy causes the eyes to deviate inward and has many causes due to the relatively long path of the nerve. Increased cranial pressure can compress the nerve as it runs between the clivus and brain stem. Also, if the doctor is not careful, twisting of the baby's neck during forceps delivery can damage cranial nerve VI.



a condition of involuntary eye movement, acquired in infancy or later in life, that may result in reduced or limited vision.The cause for pathological nystagmus may be congenital, idiopathic, or secondary to a pre-existing neurological disorder. Early onset nystagmus occurs more frequently than acquired nystagmus. It can be insular or accompany other disorders (such as micro-ophthalmic anomalies or Down Syndrome).


sleep apnea

is a contra-indication to using growth hormone


supernumerary marker chromosome

an extra, 47th autosomal chromosome


Isodicentric 15

Poor muscle tone is commonly seen in individuals with isodicentric chromosome 15 syndrome and contributes to delayed development and impairment of motor skills, including sitting and walking. Babies with isodicentric chromosome 15 syndrome often have trouble feeding due to weak facial muscles that impair sucking and swallowing; many also have backflow of acidic stomach contents into the esophagus (gastroesophageal reflux). These feeding problems may make it difficult for them to gain weight. Intellectual disability in isodicentric chromosome 15 syndrome can range from mild to profound. Speech is usually delayed and often remains absent or impaired. Behavioral difficulties often associated with isodicentric chromosome 15 syndrome include hyperactivity, anxiety, and frustration leading to tantrums. Other behaviors resemble features of autistic spectrum disorders, such as repeating the words of others (echolalia), difficulty with changes in routine, and problems with social interaction.
About two-thirds of people with isodicentric chromosome 15 syndrome have seizures. In more than half of affected individuals, the seizures begin in the first year of life.
About 40 percent of individuals with isodicentric chromosome 15 syndrome are born with eyes that do not look in the same direction (strabismus). Hearing loss in childhood is common and is usually caused by fluid buildup in the middle ear. This hearing loss is often temporary. However, if left untreated during early childhood, the hearing loss can interfere with language development and worsen the speech problems associated with this disorder. Isodicentric chromosome 15 syndrome results from the presence of an abnormal extra chromosome, called an isodicentric chromosome 15, in each cell. An isodicentric chromosome contains mirror-image segments of genetic material and has two constriction points (centromeres), rather than one centromere as in normal chromosomes. In isodicentric chromosome 15 syndrome, the isodicentric chromosome is made up of two extra copies of a segment of genetic material from chromosome 15, attached end-to-end. Typically this copied genetic material includes a region of the chromosome called 15q11-q13. Cells normally have two copies of each chromosome, one inherited from each parent. In people with isodicentric chromosome 15 syndrome, cells have the usual two copies of chromosome 15 plus the two extra copies of the segment of genetic material in the isodicentric chromosome. The extra genetic material disrupts the normal course of development, causing the characteristic features of this disorder. Some individuals with isodicentric chromosome 15 whose copied genetic material does not include the 15q11-q13 region do not show signs or symptoms of the condition.


Four ways someone could have angelman’s syndrome

maternal deletion and paternal imprinting silenced, UBE 3a mutation and paternal imprinting, paternal uniparental disomy, or imprinting defect where both maternal and paternal are silenced.


midfacial hypoplasia

middle third is too small, nose is flat, airway and inside of ears is small, upslanted eyes


epicanthal folds

names for a skin fold of the upper eyelid, covering the inner corner (medial canthus) of the eye. Epicanthic fold is sometimes found as a congenital abnormality.[1] Medical conditions that cause the nasal bridge not to mature and project are associated with epicanthic folds. About 60% of individuals with Down syndrome have prominent epicanthic folds.



a medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger (the "little finger") towards the adjacent fourth finger (the "ring finger"). Clinodactyly can be passed through inheritance and presents as either an isolated anomaly or a component manifestation of a genetic syndrome. Many syndromes are associated with clinodactyly, including Down Syndrome, Aarskog syndrome, Carpenter syndrome, Seckel syndrome, Cornelia de Lange syndrome, Orofaciodigital syndrome 1, and Silver–Russell syndrome.



a condition in which a body orifice or passage in the body is abnormally closed or absent.


Hirschsprung's disease (HD)

a disorder of the abdomen that occurs when part or all of the large intestine or antecedent parts of the gastrointestinal tract have no ganglion cells and therefore cannot function. During normal fetal development, cells from the neural crest migrate into the large intestine (colon) to form the networks of nerves called. In Hirschsprung's disease, the migration is not complete and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and pass stool through the colon, creating an obstruction. In most affected people, the disorder affects the part of the colon that is nearest the anus. In rare cases, the lack of nerve bodies involves more of the colon. In five percent of cases, the entire colon is affected. Stomach and esophagus may be affected too. Hirschsprung's disease is also often called congenital aganglionic megacolon.



a chronic symptom of mucosal damage caused by stomach acid coming up from the stomach into the esophagus. GERD is usually caused by changes in the barrier between the stomach and the esophagus, including abnormal relaxation of the lower esophageal sphincter, which normally holds the top of the stomach closed, impaired expulsion of gastric reflux from the esophagus, or a hiatal hernia. These changes may be permanent or temporary.


celiac disease

an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward. Symptoms include pain and discomfort in the digestive tract, chronic constipation and diarrhoea, failure to thrive (in children), anaemia[2] and fatigue, but these may be absent, and symptoms in other organ systems have been described. Vitamin deficiencies are often noted in people with coeliac disease owing to the reduced ability of the small intestine to properly absorb nutrients from food.



commonly known as near-sightedness, is a condition of the eye where the light that comes in does not directly focus on the retina but in front of it, causing the image that one sees when looking at a distant object to be out of focus, but in focus when looking at a close object.


alopecia areata

a condition in which hair is lost from some or all areas of the body, usually from the scalp. Because it causes bald spots on the scalp, especially in the first stages, it is sometimes called spot baldness.


hashimotos disease

an autoimmune disease in which the thyroid gland is attacked by a variety of cell- and antibody-mediated immune processes. It was the first disease to be recognized as an autoimmune disease. The most common symptoms include the following: fatigue, weight gain, pale or puffy face, feeling cold, joint and muscle pain, constipation, dry and thinning hair, heavy menstrual flow or irregular periods, depression, a slowed heart rate, and problems getting pregnant and maintaining pregnancy. The genes implicated vary in different ethnic groups and the incidence is increased in patients with chromosomal disorders, including Turner, Down's, and Klinefelter syndromes usually associated with autoantibodies against thyroglobulin and thyroperoxidase.


myeloproliferative disorder

a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions. All MPDs arise from precursors of the myeloid lineages in the bone marrow. The lymphoid lineage may produce similar diseases, the lymphoproliferative disorders (acute lymphoblastic leukemia, lymphomas, chronic lymphocytic leukemia and multiple myeloma).Most Philadelphia chromosome negative cases have an activating JAK2 or MPL mutation.[4] Mutations in CALR have been found in the majority of JAK2 and MPL-negative essential thrombocythemia and myelofibrosis.[5] [6] In 2005, the discovery of the JAK2V617F mutation provided the first evidence that a fraction of persons with these disorders have a common molecular pathogenesis.


infantile spasms

an uncommon-to-rare epileptic disorder in infants, children and adults. appears in 1% to 5% of infants with Down syndrome. This form of epilepsy is relatively difficult to treat in children who do not have the chromosomal abnormalities involved in Down syndrome.


forces affecting allele frequencies

new mutations, natural selection, genetic drift (random changes), and gene flow (addition/subtraction)



the probability of transmitting one's genes to the next generation (f=1 same as normal population, f=0 genes not passed on. Lethal and severe disorders have a low fitness (0 in case of lethal) because the individual does not live long enough or is not healthy enough to reproduce and pass on the disease allele. Fitness measures reproductive success which means survival is not the only consideration (e.g. your fitness is still low if you possess superhuman strength and health, but suffer from infertility or are an intolerable egomaniac and are unable to have biological children).


coefficient of selections

a measure of the forces that reduce fitness (s=1-f)


mutation rate (u)

frequency of new mutations at a given genetic locus; expressed as mutations/generation


autosomal dominant direct method for estimating mutation rates

when there is full penetrants (no hidden mutations), count the sases with no family history (the new mutations)=u


autosomal dominant indirect method for estimating mutation rates

For an autosomal dominant condition where the reproductive fitness (f) is zero (i.e. affected persons do not survive to reproduce and/or are infertile) then all cases represent new mutations. Since each child inherits 2 genes (each could mutate) then the incidence (I) of disease is really twice the mutation rate àà I = 2μ.


Population genetics

the quantitative study of the distribution of genetic variation in populations and how the frequencies of genes and genotypes are maintained or change. Four main evolutionary forces affect allele frequencies: natural selection, genetic drift, mutation and gene flow. Results from population genetics are used by public health scientists to predict allele (or disease) changes in populations and by health care professionals to predict disease risks for individuals.


Founder effects

a high frequency of a mutant allele in a population founded by a small ancestral group when one or more of the original founders was a carrier of the mutant allele


Genetic drift

random fluctuation of allele frequencies, usually in small populations



active selection of favorable alleles over non-favorable ones. Selection depends on fitness, a measure of the chance an allele will be transmitted to the next generation (Scale is 0-1). Natural selection generally occurs only when the trait is expressed, which means that even severe recessive alleles are not selected against in the heterozygous state. Exceptions to this statement could occur if genetic testing of asymptomatic persons identifies heterozygotes persons who then elect to not have children or terminate an affected pregnancy for instance.


Migration and Gene Flow

When populations with different allele frequencies for a disorder mix (typically seen in cases of immigration) then allele frequencies can change (affecting Hardy Weinberg estimates).


C-C chemokine receptor type 5 (CCR5)

a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. This is the process by which T cells are attracted to specific tissue and organ targets. Many forms of HIV, the virus that causes AIDS, initially use CCR5 to enter and infect host cells. A few individuals carry a mutation known as CCR5-Δ32 in the CCR5 gene, protecting them against these strains of HIV.



Disease-causing mutations are occurring all the time and do so at different rates for different disorders (and probably in different populations). In fact using the rate of 1 x 10-6 mutations / gene / generation and the fact that we have ~25,000 genes this projects for each new baby a 2.6% risk of a new mutation at one locus, which extrapolates to ~1 in 40 persons has a new mutation in their genome as compared to their parents. Note also, that these empirical estimates of mutation rates are being studied actively with NextGeneration DNA sequencing methods


Autosomal Dominant Diseases, when the fitness is not zero

μ= 1/2 F (1-f) μ=mutation rate /gene/generation F=frequency of the disease f=reproductive fitness


Autosomal recessive diseases, when the fitness is not zero

μ= F (1-f). μ=mutation rate /gene/generation F=frequency of the disease f=reproductive fitness


x-linked recessive diseases, when the fitness is not zero

μ= 1/3 F (1-f). μ=mutation rate /gene/generation F=frequency of the disease f=reproductive fitness



populations containing 2 or more subgroups which tend preferentially mate within their own subgroup. Mate selection is not dependent on the trait/disease or interest. (Example: sickle cell anemia in African Americans (AAs) has higher incidence social stratification favoring mating of AAs with other AAs, than is predicted by HWE)


Assortive mating

when the choice of mate is dependent (in part) on a particular trait (or sometimes a disease). This occurs because people tend to choose mates who resemble themselves for (language, intelligence, height, skin color, etc.). This has been observed for congenital short stature (previously called ‘dwarfism’), blindness, and deafness.



when persons marry closely-related blood relatives. This, non- random, mating practice increases matings between carriers of autosomal recessive diseases, thereby increasing the number of cases of autosomal recessive diseases in the population.


Cystic Hygroma

a congenital multiloculated lymphatic lesion that can arise anywhere, but is classically found in the left posterior triangle of the neck and armpits. This is the most common form of lymphangioma. It contains large cyst-like cavities containing lymph, a watery fluid that circulates throughout the lymphatic system. Microscopically, cystic hygroma consists of multiple locules filled with lymph. In the depth, the locules are quite big but they decrease in size towards the surface.


Characteristics of turner syndrome

Turner syndrome is a chromosomal condition that affects development in females. The most common feature of Turner syndrome is short stature, which becomes evident by about age 5. An early loss of ovarian function (ovarian hypofunction or premature ovarian failure) is also very common. The ovaries develop normally at first, but egg cells (oocytes) usually die prematurely and most ovarian tissue degenerates before birth. Many affected girls do not undergo puberty unless they receive hormone therapy, and most are unable to conceive (infertile). A small percentage of females with Turner syndrome retain normal ovarian function through young adulthood. About 30 percent of females with Turner syndrome have extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, or kidney problems. One third to one half of individuals with Turner syndrome are born with a heart defect, such as a narrowing of the large artery leaving the heart (coarctation of the aorta) or abnormalities of the valve that connects the aorta with the heart (the aortic valve). Complications associated with these heart defects can be life-threatening. Most girls and women with Turner syndrome have normal intelligence. Developmental delays, nonverbal learning disabilities, and behavioral problems are possible, although these characteristics vary among affected individuals. They also have urinary system issues and endocrine problems (hypothyroidism and gonadal dysgenesis)


What are the genetic changes related to Turner syndrome?

Turner syndrome is related to the X chromosome, which is one of the two sex chromosomes. People typically have two sex chromosomes in each cell: females have two X chromosomes, while males have one X chromosome and one Y chromosome. Turner syndrome results when one normal X chromosome is present in a female's cells and the other sex chromosome is missing or structurally altered. The missing genetic material affects development before and after birth. About half of individuals with Turner syndrome have monosomy X, which means each cell in the individual's body has only one copy of the X chromosome instead of the usual two sex chromosomes. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely absent. Some women with Turner syndrome have a chromosomal change in only some of their cells, which is known as mosaicism. Women with Turner syndrome caused by X chromosome mosaicism are said to have mosaic Turner syndrome. Researchers have not determined which genes on the X chromosome are associated with most of the features of Turner syndrome. They have, however, identified one gene called SHOX that is important for bone development and growth. The loss of one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner syndrome.


madelung deformity

usually characterized by malformed wrists and wrist bones, accompanied by short stature and is often associated with Léri-Weill dyschondrosteosis.


pectus excavatum

the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest. Pectus excavatum is sometimes considered to be cosmetic; however, depending on the severity, it can impair cardiac and respiratory function and cause pain in the chest and back.



the absence of a menstrual period in a woman of reproductive age.



kulls or noses are shorter than typical for the species. the cephalic disorder is known as flat head syndrome, and results from premature fusion of the coronal sutures (see craniosynostosis) or from external deformation (see plagiocephaly). The coronal suture is the fibrous joint that unites the frontal bone with the two parietal bones of the skull. The parietal bones form the top and sides of the skull. This feature can be seen in Down syndrome.


etiology of trisomy 21`

the high presentage of all cases of trisomy 21 in which the abnormal gamete originated during maternal meiosis I suggests that something about maternal meiosis I is the underlying cause. The older egg model suggests that the older the oocyte the greater the chance that the chromosomes will fail to disjoin correctly. also older eggs may be less able to overcome a susceptibility to nondijuction etablished by the recombination machinary.


Philadelphia chromosome

a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t(9;22)(q34;q11). The presence of this translocation is a highly sensitive test for CML, since 95% of people with CML have this abnormality (the remainder have either a cryptic translocation that is invisible on G-banded chromosome preparations, or a variant translocation involving another chromosome or chromosomes as well as the long arm of chromosomes 9 and 22). However, the presence of the Philadelphia (Ph) chromosome is not sufficiently specific to diagnose CML, since it is also found in acute lymphoblastic leukemia (ALL, 25–30% in adult and 2–10% in pediatric cases) and occasionally in acute myelogenous leukemia (AML). The exact chromosomal defect in Philadelphia chromosome is a translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 (region q34) to a part of the BCR ("breakpoint cluster region") gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome). Translocation results in an oncogenic BCR-ABL gene fusion that can be found on the shorter derivative 22 chromosome. Because the Abl gene expresses a membrane-associated protein, a tyrosine kinase, the BCR-Abl transcript is also translated into a tyrosine kinase. The activity of tyrosine kinases is typically controlled by other molecules, but the mutant tyrosine kinase of the BCR-Abl transcript codes for a protein that is "always on" or continuously activated, which results in unregulated cell division (i.e. cancer). Although the BCR region also expresses serine/threonine kinases, the tyrosine kinase function is very relevant for drug therapy. Tyrosine kinase inhibitors (such as imatinib and sunitinib) are important drugs against a variety of cancers including CML, renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). The fused BCR-Abl protein interacts with the interleukin-3 receptor beta(c) subunit. The ABL tyrosine kinase activity of BCR-Abl is elevated relative to wild-type ABL. Since ABL activates a number of cell cycle-controlling proteins and enzymes, the result of the BCR-Abl fusion is to speed up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.