Lecture 6

Chromosomal Abnormalities Chromosomal abnormalities

 Numeric

- abnormal # of sets

- abnormal chromosome number  Structural

syndromes

 Duplications

 Ring

 Centromeric fusions (Robertsonian translocations)

 Inversion

 Paracentric

 Pericentric

 Reciprocal translocations

Numeric abnormalities Polyploidy-abnormal number of chromosome sets

 only triploidy and tetraploidy have been reported

 Only triploidy survives to birth, but they die shortly after

 Mechanisms of triploidy

 Abnormal 1

 Abnormal meiosis 2

 Fertilization with 2 sperm

 Tetraploid spermatogonium or oogonium  Mechanisms of tetraploidy

 Believed to result from failure of mitotic division early in development of zygote

Aneuploids-abnormal number of chromosomes (or partial chromosomes)

 Most common type of numeric abnormality (2-3% of pregnancies)

 Most are trisomies, rare monosomies

 Most common trisomies are 21, 18 and 13

 Severe phenotype

 Monosomy of entire chromosome is almost always lethal, except X0

 Mechanisms of aneuploidys

 Chromosomal loss

 Mechanisms

 Probably due to lagging behind of one chromosome in anaphase

 From mouse studies, we know that cells are prone to chromosomal loss at the pronuclei stage before male and female nuclei fuse

 Chromosomal loss can occur in , early in development; if it does, it can result in a mosaic zygote

Mechanisms of aneuploidy con’t

 Meiotic nondisjunction at meiosis 1 or meiosis 2 (usually 1)

 Mechanisms

 Too few X-overs or X-overs close to the or predispose to nondisjunction

 Can also occur in mitotic cell division soon after fertilization

 Premature separation of sister in meiosis 1

 Rare cases of nondisjunction in both sperm and egg may result in trisomy of more than one chromosome

 The consequence of nondisjunction at meiosis 1 is different than at meiosis 2. If it occurs at meiosis 1, gamete gets both a maternal and paternal chromosome; if at meiosis 2, the gamete has 2 maternal or 2 paternal chromosomes  Nondisjunction at meiosis 1 vs meiosis 2  Common

 Trisomy 21

 95% of Downs syndrome patients

 Characteristic phenotype risk increases with maternal age (especially after 30)

 Usually occurs as nondisjunction at Meiosis 1

 4% have Robertson translocation-high risk for recurrance

 1/800 births Trisomy 21 Trisomy 21

 Growth failure  Mental retardation  Flat occiput  Dysplastic ears  Intestinal stenosis  Hypotonic muscles  Webbed toes, widely spaced  Broad flat face  Slanting eyes  Short nose  Small and arched palate  Big tongue  Short, broad hands  Congenital heart disease

 Trisomy 18

 Mental retardation, failure to thrive, severe malformations of the heart, rocker bottom feet,

 characteristic hand position

 Rarely survive to birth (1/7500 births)

 Trisomy 13

 Severe mental retardation, growth retardation, severe multiple organ malformations including cleft lip and palate, polydactyly

 1/20,000 births

anuploidies

 Next lecture

Structural chromosomal abnormalities (1/375 newborns)

 Unbalanced

 A structural chromosomal abnormality is problematic if it results in a gain or loss of the normal complement of genetic material

 Balanced

 A rearrangement is balanced if a normal complement of genetic material is maintained

 Not usually any clinical significance for the patient, unless genes are disrupted, but may have consequence for offspring  Examples of unbalanced rearrangements

 Deletions

 Mechanisms

 Chromosomal breakage and loss of fragments (terminal or interstitial)

 Unequal crossing over between misaligned homologous chromosomes or sister chromatids

 Eg: Cri du chat – deletion of 5Q

 Moon face

 Hypertention

 Characteristic cry

Results in haploinsufficiency in 1/7000 live births  Contiguous gene syndromes

 Commonly observed deletions that involve more than one gene

 eg:

 Wilms tumor

 Retinoblastoma

 Prader-Willi / Angelman

 Langer-Giedion

 Duplications

 Mechanisms

 Unequal crossover between misaligned chromosomes

 Chromosomal imbalance due to parental translocation or inversion

Abnormal clinical phenotype depending on region duplicated

 Marker chromosomes

 Unidentified small chromosomes that may contain little more than a centromere, so have little clinical significance. Larger marker chromosomes may have genetic material and may cause imbalance. If detected prenatally, significance is hard to assess. Their chromosomal origin is hard to identify by banding techniques—must use FISH  Ring chromosomes  If larger marker chromosomes lack , the ends fuse to form rings.

 They can go through mitosis or meiosis, but if cross-over occurs, the chromatids may get tangled and break

 One arm is missing and other is duplicated in a mirror image

 Mechanism is unknown, but believed to be related to misdivision of centromere in Mieosis 2 or X-over close to the centromere

 Actually have 2 , but hard to distinguish

 Most common is long arm of X in some Turners syndrome

 Dicentric chromosomes  Results when 2 chromosomes fuse ends to form a chromosome with 2 centromeres  Can get through meiosis if both centromerers travel in the same direction at anaphase or in some cases, one centromere is not functional Examples of balanced rearrangements

 Robertsonian translocation

 2 acrocentric chromosomes fused at the centromere

 Loss of ribosomal DNA, but these genes are duplicated so no clinical significance

 Insertion

 Insertion of a segment of DNA into a nonhomologous chromosome  Inversions

 2 breaks and segment is reconstituted in the reverse orientation at the same position

 2 types

 Paracentric-doesn’t involve centromere

 Pericentric-inverted segment includes the centromere  Reciprocal translocations

 Breakage of nonhomologous chromosomes with reciprocal exchange

 Seen in 1/600 newborns Meiosis in individuals with balanced chromosomal rearrangements  Balanced chromosomal rearrangements usually have no clinical significance for the individual who inherits them unless the rearrangement happens to disrupt a gene

 HOWEVER, they are at high risk of producing unbalanced gametes and therefore abnormal offspring Robertsonian translocation at meiosis t(14;21) Robertsonian translocation at meiosis t(21;21) Chromosomal inversion Inversion At meiosis

Paracentric

Pericentric Chromosomal inversion at meiosis cont’d

 Crossover is usually suppressed in the loop, but if it occurs, there are significant consequences to gametes

 Unbalanced resulting from paracentric inversion are not usually viable so have no clinical significance

 From paricentric inversions there may be small imbalances that are compatable with live, but cause abnormalities—difficult to predict outcome for pregnancy

Reciprocal translocation at meiosis Reciprocal translocation at meiosis cont’d

 At meiosos a quadravalent forms that can be seen at anaphase in 1 of 3 ways (alternate, adjacent1 or adjacent 2 (see illustration)

 Abnormal gametes may result

General comments on chromosomal anomalies

• Overlap in clinical phenotype presumably because many genes are involved in organ development – Low birth weight, short stature, failure to thrive – Mental retardation – Dysplastic facies – Abnormal dermatoglyphics – Heart, cerebral and genitourinary malformations Why are trisomies abnormal??