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What is the difference between genetic and genomic medicine?

Genetics = study of genes and their role in inheritance; the way certain traits are passed from one generation to the next Human genetics = biological variations in humans medical genetics = biological variations in humans as it relates to health and disease clinical genetics = biological variations in humans as it relates to health and disease and how to diagnose, treat, and manage these diseases Genomics = study of an individual's genome (all of their genes) including the interaction of those genes with each other and with the persons ENVIRONMENT (complex diseases involving genes + environment) **all medical conditions that are treated are mixture of genetics and environment EXCEPT trauma


Explain how the human genome project as expanded the field of medical genetics and its impact on medicine

HGP goal = to sequence human genome (DNA sequence) in order to identify cause and genetic component of human disease In doing so HGP has let to: biotech based products, HAPMAP project (common variant, common disease) for identifying human gene variations across populations, ethical/legal/social issues related to genetic information, encyclopedia of DNA elements (ENCODE) Future goals = cancer genome atlas, personalized medicine, rare disease project GWAS (genomic wide association studies) = rapid scan of genomes for genetic variants for specific diseases 23andMe = direct to consumer haplotyping of personal genomes


What clinical genetic principals should ever health professional know?

1. family hx is the number one diagnostic tool for genomic disease 2. genetic terms 3. diseases common to specific ethnic groups 4. social/ethical/legal issues 5. environmental, behavioral and genetic factors 6. resources available


Describe the roles of genetic professionals (clinical geneticists, genetics counselor, clinical genetics lab specialist, medical biochemical geneticist. PCP)

1. clinical geneticist: = a physician who provides comprehensive diagnostic, management, treatment, risk assessment, and counseling for a patient at risk of having a genetic disorder 2. Genetic Counselor = a health professional (masters degree) who assists patients in understanding medical, psychological, and familial implications of disease--uses family history to provide information on inheritance, testing, etc. and counsel the patient to promote informed decision 3. Clinical genetics lab specialist = PhD, MD, DO who runs the genetic testing for chromosomal, molecular, and metabolic conditions 4. Medical biochemical geneticist = MD specializing in treating patients with inborn errors in metabolism 5. PCP = recognizing the signs and symptoms of single gene/chromosomal and mulifactorial diseases; in complex multifactorial diseases the should use genetic tests to guide treatment plans


What are the consequences of not identifying a genetic disease?

1. decreased quality of life (because eventually the disease symptoms come on) 2. decreased lifespan 3. risk family members not identified 4. children left behind with no knowledge of risk


What is the basic chromosome structure, organization, and anatomy?

=23 chromosomes (22 autosomes, 1 sex chromosome) 1. Structure: Typical chromo = in metaphase = 2 daughter molecules of DNA produced during S-Phase of interphase of cell cycle, separately folded and condensed along their protein axis to produce 2 sister chromatids attached at a centromere # of chromosomes = # of centromeres # of strands of DNA (molecules) = # of chromatids have associated proteins that are crucial to their structure (fragile when proteins are absent); Autosome = chromosome pa with one of each pair from the maternal origin, and one of each pair from paternal origin Sex = remaining pair; XX = female, XY = male 2. Organization = chromos are best visualized at METAPHASE after DNA is replicated and present in a condensed state. **chromos are less condensed and longer at prophase than metaphase **each chromosome pair is identified on the basis of size, shape, and banding pattern produced by a particular staining process 3. Anatomy p = short arm ('petite' ) q = long arm Metacentric, Acentric, or submetacentric


What is the difference between metacentric, acentric, and submetacentric chromosomes?

Metacentric = centromere is in the middle Acrocentric = centromere is near one end (leading to a short p arm which ends in structures called satilites); includes chromosomes 13, 14, 15, 21, 22, Y (but Y isn't involved in Robertsonian translocations) Submetacentric = centromere is somewhere between metacentric and acentric


What is the process of preparing a karyotype?

1. Blood cells placed in tissue culture medium with phytohemagluttinin (PHA) to agglutinate BC and stimulate lymphocyte to divide 2. Separate off RBC (want only WBC since RBC dont have any nuclear material) and incubate WBC for 3 days 3. Add Colchicine: blocks spindle formation so that cell division is blocked at metaphase; chromosomes condense, but do not organize along metaphase plate; nuclear membrane breaks down 4. Cells placed in hypotonic saline (for lysing) 5. Cells are fixed, stained, and phtographed under microscope Result: each normal metaphase chromosome can be seen as 2 chromatids held together at the primary construction site (the centromere); the specific point of attachments = the kinetocore (the site of spindle fiber attachment for drawing chromatids to opposite poles during cell divison) **** THIS IS THE NORMAL KARYOTYPING PROCESS. FOR HIGH RESOLUTION KARYOTYPING, STOP DIVISION IN PROPHASE so that the chromosomes are less condensed and longer (easier to identify more bands/chromosomes)


What is the purpose/what are the characteristics associated with: chromosome banding? What are the different types of chromosome banding and how do the results present? How are specific genes identified on chromosome bands?

= karyotyping Band = part of a chromosome that is clearly distinguishable from its adjacent segments by appearing darker or lighter or by 1 or more banding techniques **each band DOES NOT identify a unique gene, but rather a unique segment which contains HUNDREDS of genes; chromosomes are identified and aligned in pairs based on accepted nomenclature (normal banding pattern; called ideogram) into karyotypes "46XX or 46XY = normal" 1. Giesma banding = G band; most widely used (+/- for giesma) , allows for identification of DELETION OR DUPLICATION of 4mBP (not for small deletions) Dark bands = more highly condensed regions, less transcriptionally active (those genes expressed during development.. tissue specific genes) Light bands = less condensed; more euchromatin and location of more transcriptionally active genes involved in day to day activity of genes/cellular activity (ie: house keeping genes) 2. High Resolution Banding: uses compounds that interfere with condensation, leading to longer chromosomes (less condensed) = pictured at prophase/prometaphase Classification of chromosome banding: landmark = consistent and distinct morphological feature for identifying a chromosome region = area between two landmarks to identify a particular band need: 1. chromosome number 2. chromosome arm (p vs q) 3. region number 5. band number (1 = closest to centromere and increase in number as move outward)


What is the purpose/what are the characteristics associated with: Fluorescent In Situ Hybridization (FISH)

FOR: recognizing absence/presence of a particular DNA sequence Molecular probes are constructed to be precisely complementary (cDNA) to a specific sequence of a target DNA; DNA strands are denatured, exposing the nucleotide sequence of each strand, probe added and strands reanelaed, allowing the probe and DNA to complement and then the DNA now is fluorescently labeled for identification FUNCTION = to detect chromosome or specific chromosome segments; for recognition of translocations, deletions, or other STRUCTURAL rearrangements (sort of like karyotype, but more microscopic) Used for screening of prenatal amniotic fluid cells for: -anaploidy (trisomny 13,18,21,X,Y) -ID baby sex -translocations -marker chromosomes -micrdeletion syndromes (ie: di georges velecardiofacial, cri du chat) **different FISH probes can be added to identify multiple targets at the same time!


What is the purpose/what are the characteristics associated with: Array based comparative genomic hybridization (aCGH)

= used for detection and map copy numbers changes in the regions of the genome -DNA tested and reference DNA are differentially labeled and hybridized to the array. The ratio of the fluorescence of the test to reference signals are then calculated and then from this the copy and changes in the test sample relative to the reference sample can be determined USES: deletions, duplication, subtelomeric deletions, aneuploidy, genetic instability in cancer genomes (basically everything that karyotypes can do plus some) LIMITATIONS: CANNOT DETECT balanced translocations (reciprocal or inversions) or mosaicism


Describe what a numerical chromosomal abnormality is

= ploidy haploid = normal gamete; one member of each chromosome pair (normal = 23) diploid = normal autosome; 2*haploid triploid = number of chromosomes = 3*haploid due to extra set of chromosomes (n = 69); can be due to paternal = double fertilization o fertilization with a diploid sperm; or maternal = fertilization of a diploid egg anaploidy = any chromosome number that is not an exact multiple of the haploid number = extra copy of a single chromosome (trisomy) or absence of a single chromosome (monosomy)


How does anaploidy occur?

= result of a nondisjunction (failure of chromosomes to separate normally during division (meiosis or mitosis) Meiotic non-disjunction: = increased risk with increased maternal age (can be meiosis I or II) Meiosis I: gametes formed have BOTH parental chromosomes that failed to separate, or NEITHER (nondisjunction occurs during anaphase I) Meiosis II: gametes contain 2 copies of ONE parental chromosome (maternal or paternal) or NONE


What are structural abnormalities?

= rearrangements in one or more chromosomes; one chromosome involved = deletions, duplications, inversions, isochromosome formation, ring chromosome formation. two or more chromosomes involved = insertion of material from one chromosome to another, or translocation or exchange of material between two chromosomes


what is the difference between a terminal and interstitial deletion/duplication?

terminal = loss or doubling of material at the end of a chromosome interstitial = loss or doubling of material within a chromosome


what is the difference between a paracentric and pericentric inversion?

paracentric = dont include the centromere; 2 breaks in one arm (both breaks are either above or below the centromere, so that an inversion occurs in only ONE arm of the choromsome (p or q))

pericentric = include the centromere; one break in each arm (first break above the centromere, second break below the centromere and then it inverts ABOUT the centremere--PERI) inversion suggests reversal of the orientation of the intervening portion between the breaks



What are isochromosomes? what type of abnormality? 

a type of structural abnormality in which there is a complete absence of one of the chromosome arms (ie p or q) and complete duplication of the other chromosome arm. 


What are translocations? What is a balanced translocation vs an unbalanced translocation? what is a robertsonian translocation vs. a reciprocal translocation? 

In both: can be balanced or unbalanced; 

Balanced = no essential chromosomal material is lost and no genes are damaged during breakage and reunion... clinically normal; BUT the balanced translocation is a CARRIER and is at risk of having unbalanced offspring; 

Unbalanced = loss of genetic information 


1. Reciprocal = exchange of chromosomal material betnween two NON HOMOLOGOUS CHROMOSOMES; 3 outcomes are possible: 1). normal gametes 2). Balanced translocation 3). Unbalanced gamete with 1 extra chromosomal segment (partial trisomy) and a deletion of other chromsome segments (partial monosomy); Many unbalanced gametes are non-viable and result in early embryonic loss or spontaneous miscarriage 


2. Robertsonian = "centric"; translocation between two ACROCENTRIC chromosomes (13,14,15,21,22,X,Y) by fusion at the centromere with LOSS OF THE SHORT ARM AND SATELITES 

Becasue the short arms of all 5 pairs of acrocentric chromsomes have multiple copies of genes for rRNA, loss of short arms of acrocentric chromosomes is not deleterious; 

But, consequence of major chrosomal abnormalities = spontaneous abortion: 

Trisomy 16 = most common chromosomal defect leading to spontanous abortion; the earlier in gestation that the abnormality occurs, the higher the liklihood that it is a chromosomally abnormal an dmore fatal; 


What are the clinical characteristics of trisomy 21? 

= Down Syndrome:

slanted palpebral fissurs (upward slanting), depressed nasal bridge (flat face) hearing and vision impairment, slower development (developmental milestones delayed), mental retardation (all patients!!!) congenital heart defects (major mortality); duodenal atresia, simian crease (single plamar due to hypotonia), hypotonia,  excess flap of skin on back of neck;


Patients reach developmental milestones slower than children who dont have downs syndome (ie: sitting, walking, talking); no "cure" for down syndrome, just treat the symptomes (ie: heart problems, duodenal atresia, etc.) 


Best outcome for pts: to live a normal family life in own home; all schools are required to have services for down syndrom patients (in regular classrooms = main streaming) 


**most common cause of genetic mental retardation!!! 


What is the etiology of trisomy 21? 

= due to a chromosomal anomaly:

1. 95% of time = Nondisjunctional trisomy of maternal meiosis origin

2. mosaicism = nondisjunction occurs in a cell division AFTER fertilization (mitotic) and leads to two populations of cells: some with 46 chromos, some with 47 chromos (trisomnic group)

3. robertsonian translocation = when all or part of the chromosome 21 becomes attached to another chromosome; result = unbalanced. MATERNAL AGE IS NOT ASSOCATED WITH TRANSLOCATION!!! (only associated with non-disjunction) 


The recurrance/general risk: increases with increased maternal age EVEN THOUGH THE INCIDENCE INCREASES WITH DECREASED MATERNAL AGE (becuase more young people are having babies) 


reccurance risk: depends on: 1. etiology 2. parent sex:

if due to nondisjunction: recurring risk = 1% or if maternal > 35, 2%;

if due to translocation: karyotype BOTH parents:  if mom carrier = 10-15%, if father carrier = 5%; if a BALANCED 21: 21 translocation (both 21's on one chromo, on a parent) then 100% of progeny will be trisomy


What are the clinical characteristics of trisomy 18? 

= Edwards syndrome;



-decreased fetal activity

-single umbilical artery

-growth retardation




-microcephaly and micrognathia


-cleft lip/palate

-CLENCHED FIST (overlapping 3rd/4th fingers)

-Rocker bottom feet 

-hypoplastic sternum (missing 12th ribs) 

-horseshoe kidney 

-malformed bowel 




What is the etiology of edwards disease? 

= trisomy 18; 

due to: chromosomal anomaly

1. nondisjuncitonal trisomy 

2. mosaicism (has a longer survival)


Recurrance risk: 

in non-disjunction cases: <1%

more common in females than males 

**most non-disjunction cases die from spontaneous abortions 


What are the clincal characteristics of trisomy 13? 

= "P" = patau

cleft liP/Palate


Polycystic kidney


also get: 

abnormal midfacial and forebrain devleopment, intrauterine growth retardation, micrognathia, severe mental retardation (due to holoprosencephaly); only 5% survive first 6 months 





what is the etiology of patau syndrome? 

= trisomy 13

= due to a chromosomal anomaly 

1. nondijunctional trisomy

2. mosaicism

3. translocation

Recurrance Risk of non-disjunction = <1%  (due to spontaneous abortion) 


What are the clinical manifestations of triploidy? 

VERY growth retard (if survive and born after 28 wks)

CYSTIC HYDATIFORM (large placenrta with masses resembling grapes.."moles")

simian crease and syndactyly of 3rd and 4th fingers

atrial and ventricular septal defects

skeletal asymmetry and variable psychomotor retardation (in mixoploidy cases) 

ALL CASES OF FULL TRIPLOIDY = stillborn or early neonatal death; 



What is the etiology of triploidy? 

= all chromosomes extra (69) or 46 chromosomes but all from dad. 

= Chromosomal Anomaly

  • Most cases paternally derived 

  • 66% dispermy 

  • 24% diploid sperm 

  • 10%diploid ovum 

  • 60% are 69, XXY; most of remainder is 69, XXX *usually only one maternal X chromosome remains active
  • Maternal age not a factor
  • More than 99% lost in very early pregnancy
  • Accounts for ~20% of abnormal chromosomal spontaneous miscarriages
  • 2% of all conceptions 


What test detects microdeletions? 



What are the clinical characteristics of Velocardiofacial syndrome? 

= DiGeorge's Syndrome

"CATCH 22" Cleft palate Abnormal face Thymic aplasia (T-cell deficiency) Cardiac defects Hypocalcemia (secondary to parathyroid aplasia) DUE TO DELETION ON CHROMO 22


Velopharyngeal incompetence

  • Cleft palate 

  • Speech & feeding problems

Cardiac Defects

  • Tetralogy of Fallot 

  • Interrupted aortic arch 

  • Ventricular septal defect 

  • Truncus arteriosus

Facial Appearance


  • Asymmetric crying facies 

  • overfolded ears
  • micrognathia
  • recessed jaw
  • bulbous nasal tip
  • long face

Small or absent thymus gland (immunodeficiency)

Learning Problems


  • Requires multidisciplinary approach  monitor serum calcium, lymphocytes, & ultrasounds renal and heart in neonatal perior



Karyotype, FISH, or CGH for diagnosis


What is the etiology of velocardiofacial syndrome (DiGeorge)? 

  • >95% - 22q11 microdeletion 

  • ~94% de novo deletion 

  • 6% inherited deletion 

  • Remaining 5%

    • Smaller 22q11.2 deletion 

    • Chromosomal rearrangement of 22q11.2

      TBX1 mutation​

  • Recurrence Risk 

    • De novo - minimal 

    • 50% if inherited (AUTOSOMAL DOMINANT) 




What are the clinical characteristics of 47XYY? 

="hyper males"

  • Phenotypically Normal 

  • Fertile 

  • Dull mentality (decreased IQ) 

  • Explosive behavior, behavioral problems 

  • Accelerated growth mid childhood 

  • Tall, thin stature 

  • Increased length vs breadth 

  • Narrow head 

  • Long fingers and toes 

  • Facial asymmetry: large teeth, long ears, prominent glabella 

  • Poor fine motor coordination (occasional fine intentional tremor) 

  • Acne 

  • Tall stature not apparent until 5 or 6 

  • Poor development of pectoral and shoulder girdle musculature 

  • Distractability, hyperactivity and tempor tantrums
  • Not juvenile delinquents