Chromosome Abnormalities

Human Chromosome Abnormalities

Constitutional: present at time of conception.

Acquired: occurring at a later time point; malignant conditions.

Two types:

(1) Numerical

polyploid: whole set of chrom. (triploid 3n, tetraploid 4n)
aneuploid: in individual chrom. (trisomic 2n+1, monosomic 2n-1)

(2) Structural

interchromosomal

reciprocal translocation – translocation resulting from breaks on two different hromosomes and a subsequent exchange of material. Carriers of reciprocal translocations maintain the normal number of chromosomes and normal amount of chromosome material.
robertsonian translocation – translocation in which the long arms of two acrocentric chromosomes are fused at the centromere; the short arms of each chromosome are lost. The translocation carrier has 45 chromosomes instead of 46 but is phenotypically normal because the short arms contain no essential genetic material.

Intrachromosomal

Deletion – loss of chromosome material. Opposite of duplication (see below).
Ring – ends of chrom. Lost and the new ends fuse together.
Inversion – two breaks occur, followed by reinsertion of the chromosome segment, but in reversed order.

Paracentric– inversion that does not include centromere.
Pericentric – inversion that includes the centromere.

Duplication – presence of an extra copy of chromosome material.

Numerical Abnormalities

Polyploidy (2-3%)

Triploidy

polyspermy – fertilization of egg by 2 sperm (2/3)
fertilization between normal haploid and a diploid gamete (1/3)
characterization: fusion of fingers, large placenta; most lost by birth.

Autosomal Aneuploidies

Trisomy 21 (Down Syndrome)

95% due to meiotic error (non-disjunction)
3-4% due to robertsonian translocation
1-2% due to mosaicism (mitotic non-disjunction)
incidence: 1/700 live births
characterization: low muscle tone, single palmar crease (50%), congenital heart defect (40%), leukemia (1%).
Chromosome 21: smallest chromosome (1500 genes)

Trisomy 13

brain malformation
extra digit
incidence: 1/10,000 live births
90% die within 1 year

Trisomy 18

Low muscle mass (very thin)
Overlapping fingers (clinching of fists)
Incidence: 1/8,000 live births

Origin of Numerical Abnormalities

Polyploidy

triploidy = dispermy
tetraploidy = failure of 1^st cleavage division

Aneuploidy

nondisjunction in meiosis or mitosis (mosaicism); 90% due to nondisjunction in M1
result from anaphase lag
maternal age is strong predisposing factor

Structural Abnormalities

Interchromosomal

reciprocal translocations

Mutual exchange of chrom. material between 2 chromosomes.

Individual will be clinically normal (balanced translocation).

Offspring at Ý risk of having unbalanced chrom.

robertsonian translocations

Exchanges (centric fusions) between acrocentric chromosomes
3% of Down’s results from unbalanced robertsonian translocations

Depending on how a balanced 14/21 translocation is inherited offspring can be normal, balanced translocation carrier, or have Down’s syndrome.

Fetuses with monosomy 1 are non-viable.

Intrachromosomal

Deletion and microdeletion

Loss of part of a chromosome.
Terminal deletion = involves telomere.
Interstitial deletion = involves region within the chromosome.
Results in monosomy of that segment of the chromosome.

Cri-Du-Chat Syndrome – deletion of short arm of chromosome 5.

Microdeletions = very small deletions

Congential heart defect = 22q
Prader-Will and Angelman = 15q

Duplication

Gain of part of a chromosome.
Results in trisomy of that segment of the chromosome.

Charcot-Marie-Tooth Syndrome – duplication of part of chromosome 17.

Inversion

Segment of chromosome is inverted end to end.

Pericentric = includes the centromere.

Paracentric = doesn’t include the centromere.

Though individual is normal offspring at Ý risk of having unbalanced chromosome.

Ring Chromosome

Breaks in each of the arms of the chromosome.

Population Cytogenetics

0.5% of live births have chromosome abnormalities

Most common Þ trisomy 21, 18, 13; sex trisomies; structural rearrangements

Not all fetuses survive

15% of all clinically recognized pregnancies Þ spontaneous abortion, 50% due to chromosome abnormalities

Cancer Cytogenetics

Acquired chromosomal abnormalities occur in most malignant conditions.

Philadelphia Chromosome (translocation between 9/22) – occurs in malignant cells of most patients with Chronic Myelogenous Leukemia (CML)