Lecture 6
Chromosomal Abnormalities Chromosomal abnormalities
Numeric
Polyploidy- abnormal # of chromosome sets
Aneuploidy- abnormal chromosome number Structural
Deletion syndromes
Duplications
Ring chromosomes
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 meiosis 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 mitosis, 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 centromere or telomere predispose to nondisjunction
Can also occur in mitotic cell division soon after fertilization
Premature separation of sister chromatids 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 aneuploidies
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
Sex chromosome 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 telomeres, 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
Isochromosomes 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 centromeres, 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??