Chromosomal Abnormalities

Question 1

Describe the events in meiosis that produce genetic variability among offspring

Answer 1

1. Meiotic recombination (crossing over) in Prophase I
2. Independent assortment

Question 2

Differentiate between the reproductive consequences of nondisjunction events in meiosis I versus meiosis II

Answer 2

Meiosis I - all the gametes will be abnormal. Half of the gametes will have two homologous chromosomes of a single while half the gametes will lack those chromosomes completely.

Meiosis II - half the gametes will be normal and half will be abnormal. Of the abnormal gametes, half will an extra sister chromatid and half will lack that chromosome altogether.

Question 3

Describe the relationship between meiotic recombination (crossovers) and chromosome nondisjunction

Answer 3

Crossing over that occurs too far from the centromere causes the spindle attachments and segregation during meiosis I to be less effective.

Crossing over too close to the centromere, or having too many chiasmata results in the homologs becoming entangled. Reduced or absent recombination increases the risk of nondisjunction.

Question 4

Down Syndrome

Answer 4

Trisomy 21

• Hypotonia as a newborn
• Short stature
• Brachycephaly (a wide head)
• Flat occiput (flat back of the head)
• Short nect with loose skin on the nape
• Flat nasal bridge
• Low set, folded ears
• Brushfield spots around the iris (white or gray/brown spots due to aggregation of connective tissue)
• Epicanthal folds and upslanting palpebral fissures (the opening for the eye between the upper and lower eyelids)
• Furrowed, protruding tongue
• Short, broad hands often with a transverse palmar crease
• Incurved fifth digits (aka clinodactyly)
• Wide gap between the first and second toes
• ​Intellectual disability
• Congenital heart defects
• Duodenal atresia
• Tracheoesophageal fistula

Question 5

Edwards Syndrome

Answer 5

Trisomy 18

• Prominent occiput
• Receding jaw
• Malformed and low set ears
• Short sternum
• Fists clench with 2nd and 5th digits overlapping 3rd and 4th digits
• Rocker-bottomed feet with prominent calcaneous bones
• Single palm creases with arch patterns on digits
• Hypoplastic nails
• Intellectual disability
• Failure to thrive
• Severe malformation of the heart
• Hypertonia

Question 6

Patau Syndrome

Answer 6

Trisomy 13

Infants born with Patau generally do not survive past year 1

• Sloping forehead
• ​Microccephaly
• Wide, open sutures
• ​Micropthalmia
• Iris Coloboma (holes, defects in iris)
• Absence of the eyes
• Cleft lip
• Cleft palate
• Hands and feet may have polydactyly
• Rocker-bottomed feet
• Transverse palmar creases
• Fists clench with 2nd and 5th digits overlapping 3rd and 4th digits
• Growth retardation
• Severe intellectual disability
• Severe central nervous system malformations
  
  • Arhinencephaly (absence of olfactory bulbs, tracts or nerves)
  • Holoprosencephaly (failure of embryonic forebrain to develop into 2 hemispheres)
• Congenital heart defects
• Urogenital defects

Question 7

Klinefelter Syndrome

Answer 7

(47,XXY)

Develop as males

• 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

Question 8

47,XYY Syndrome

Answer 8

• 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

Question 9

Turner Syndrome

Answer 9

45,X

Develop as females

• ≥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

Question 10

Incidence of Trisomy 21

Answer 10

~ 1/830 live births

Question 11

Incidence of Trisomy 18

Answer 11

~ 1/7,500 live births

Question 12

Incidence of Trisomy 13

Answer 12

~ 1/22,700 live births

Question 13

Mosaicism

Answer 13

Defined as two or more chromosome complements present within a single individual

• commonly caused by nondisjunction in an early post-zygotic mitotic division
• effects on development vary with the timing of the nondisjunction event, the nature of the chromosomal abnormality, and the tissues affected
• germ line mosaicism can result from a mitotic nondisjunction event in a germ cell precursor

Question 14

Mechanism of common chromosomal structural rearrangements

Answer 14

All chromosomal structural rearrangements require double strand breaks of the DNA and can be induced by a variety of DNA damaging agents such as ionizing radiation.

Duplications, deletions, inversions, insertions and translocations all appear to have breakpoints in regions of chromosomes in which repeated sequences are prevalent.

Structural rearrangements can be inherited and can also lead to further rearrangement during meiosis

Question 15

Acrocentric chromosomes

Answer 15

13, 14, 15, 21, 22, Y

p (short) arm is so short that it is hard to observe, but still present

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

Question 16

Types of chromosomal structural abnormalities

Answer 16

Balanced; unbalanced

Question 17

Balanced structural abnormalities

Answer 17

normal complement of chromosomal material

1. Inversions
2. Reciprocal translocations
3. Robertsonian translocations

Question 18

Chromosomal inversion

Answer 18

One chromosome undergoes two double strand breaks 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 gene complements and often produce no phenotypes in carriers of the rearrangement

However, inversions may lead to the production of abnormal gametes during meiosis

Question 19

Paracentric inversion

Answer 19

Excludes the centromere

If a crossover occurs within the inverted region of a paracentric inversion, both dicentric (two centromeres) bridges and acentric chromosomes can be generated, leading to chromosome breakage or loss

Observed risk of producing live offspring with unbalanced chromosomal complement is ~0; gametes are often not compatible with life

Question 20

Pericentric inversion

Answer 20

Spans the centromere

Crossovers within the inverted region can produce duplications and deletions due to looping during crossover

Sample karyotype: 46, XX inv(9)(p13q13)

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

Question 21

Reciprocal translocation

Answer 21

Results from the breakage and rejoining of nonhomologous chromosomes, with a reciprocal exchange of the broken segments

When the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis, a quadrivalent figure is formed
At anaphase, these chromosomes may segregate in one of three ways:

Alternate segregation: produces gametes that have either the normal chromosome complement or two reciprocal chromosomes, both of which are balanced
Usual form of segregation
Adjacent-1 segregation – unbalanced gametes
Adjacent-2 segregation – unbalanced gametes

The risks to offspring depend on the specific translocation, but the general empirical risk is 5-10% lethality

Question 22

Robertsonian translocation

Answer 22

Fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (containing rDNA repeats).

Result in the reduction of chromosome number

Still considered balanced rearrangements because the loss of some rDNA repeats is not deleterious

Carriers of Robertsonian translocations are phenotypically normal, but these rearrangements lead to unbalanced karyotypes for their offspring, resulting in monosomies and trisomies

The most common example is a translocation involving chromosomes 14 and 21, karyotype 45, XX or XY der(14q;21q)

Question 23

Unbalanced structural abnormalities

Answer 23

abnormal chromosomal content

1. Deletions
2. Duplications
3. Isochromosomes
4. Marker (ring) chromosomes

Question 24

Chromosomal deletion

Answer 24

Loss of genetic information that can arise by simple chromosome breakage and rejoining, unequal crossing over between misaligned homologous chromosomes or sister chromatids, or by abnormal segregation of a balanced translocation or inversion.

Terminal deletion
Interstitial deletion

The clinical consequences of deletions reflect haploinsufficiency, where the contribution of the remaining normal allele is unable to prevent disease
Severity of the phenotype depends on the size of the deletion and the number of genes affected
Sample karyotype for a deletion: 46, XY del (5)(p15)

Describes a deletion of chromosome 5 in the region denoted p one-five (Cri-du-chat syndrome)

Question 25

Chromosomal duplication

Answer 25

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

Question 26

Isochromosomes

Answer 26

Refers to a chromosome in which one arm is missing and the other arm is duplicated in a mirror-like fashion ## Footnote Two models for the formation of this rearrangement: 1) mis-division through the CEN in meiosis II 2) exchange between one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere * most common isochromosome is one involving the long arm of the X chromosome * small percentage of Down syndrome patients have this rearrangement (sometimes written as 21q21q translocation) * 100% of the viable offspring of a carrier of isochromosome 21 are abnormal

Question 27

Ring chromosome

Answer 27

Chromosome fragment that circularizes and acquires kinetochore activity for stable transmission to daughter cells Also called a marker chromosome Sample karyotype: 46, XY r(13)(p11q34) Male with a supernumary ring chromosome derived from the p11 to q34 region of chromosome 13

Question 28

Two most common leukemia translocations

Answer 28

t(9;22) for chronic lymphocytic leukemias (CML) t(15;17) for acute myeloid leukemia (AML)

Question 29

Wolf-Hirschhorn syndrome

Answer 29

del(4p16.3) facial clefting prominent ears microcephaly, intellectual disabilities

Question 30

Cri du chat syndrome

Answer 30

del(5p15.2) microcephaly characteristic cry seizures, intellectual disabilities

Question 31

Williams syndrome

Answer 31

del(7q11.2) The majority of cases are due to random events at fertilization. If someone with Williams syndrome has a child, there is a 50% chance it will be passed to that child. Distinctive "elf-like" features. Includes wide mouth, full lips, short flat nose, full cheeks, and wide-spaced teeth. Most patients show mild to moderate intellectual disability, though there is a wide range of mental capacity from severe intellectual disability to normal intelligence. Emotionally, a notable feature of children with Williams syndrome is their high **sociability and empathy**. Attention deficit hyperactivity disorder **(ADHD)** is common in children and adolescents.

Question 32

Langer-Giedion syndrome

Answer 32

del(8q24.1) Very rare disease that causes bone abnormalities and distinctive facial features ``` Tricho-rhino-pharangeal syndrome multiple exostoses (benign bone tumors) ```

Question 33

WAGR syndrome

Answer 33

del(11p13) * *Wilms tumor **- rare form of kidney cancer * *Aniridia** - absence of iris * *Genitourinary anomalies **- more in males * *Intellectual disabilities** - depression, anxiety, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD)

Question 34

Beckwith-Wiedemann syndrome

Answer 34

dup(11p15.5) (paternal) Classified as an overgrowth syndrome overgrowth omphalocele - opening in the wall of the abdomen predisposition to Wilms, other tumors

Question 35

Angelman syndrome

Answer 35

del(15q11-q13) (maternal) primarily affects the nervous system delayed development intellectual disability severe speech impairment problems with movement and balance (ataxia) recurrent seizures (epilepsy) small head size (microcephaly) Delayed development becomes noticeable by the age of 6 to 12 months, and other common signs and symptoms usually appear in early childhood

Question 36

Prader-Willi syndrome

Answer 36

del(15q11-q13) (paternal) hypotonia (weak muscle tone) hypopigmentation (fair skin and light colored hair) hypogenitalism obesity (due to hyperphagia)

Question 37

Contiguous gene syndrome

Answer 37

abnormal phenotypes caused by over-expression or loss of neighboring genes Ex: Velocardiofacial Syndrome and DiGeorge Syndrome

Question 38

Miller-Dieker syndrome

Answer 38

del(17p13.3) 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) feeding difficulties Seizures usually begin before six months of age, and some occur from birth. Typically, the smoother the surface of the brain is, the more severe the associated symptoms are.

Question 39

DiGeorge syndrome

Answer 39

del(22q11.2) Poor development of several body systems absent or hypoplastic thymus and parathyroid glands congenital heart disease poor immune system development cleft palate

Question 40

Velo-Cardio-Facial syndrome

Answer 40

del(22q11.2) Comes from velum (palate) cardio (heart) and facial cleft 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 speech and feeding problems

Question 41

Charcot-Marie-Tooth Disease

Answer 41

* 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)

Question 42

Mechanisms that lead to Down Syndrome

Answer 42

•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

Question 43

Uniparental Disomy

Answer 43

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 Two alleles from same parent, but affected phenotype due to silencing of gene in imprinted region