Learning Outcomes
Be familiar with the major classes of chromosome disorders
Abnormal chromosome segregation
Caused by nondisjunction
Aneuploidy and uniparental disomy
Recurrent chromosome abnormalities
Caused by recombination at segmental duplications (regions and breakpoints are the same)
Duplication/deletion syndromes and copy number variation
Caused by NAHR at repeated sequences
Nonrecurrent chromosome abnormalities
Genetic disorders caused by duplications or deletions with variable breakpoints.
Not much is known about the origin
Understand how changes in gene dosage can lead to genetic disorders
For many disorders, having one too little or one too many copies of a gene is a problem.
Not all genes are dosage sensitive (for some, having 1 copy is enough).
Understand the causes of Down Syndrome and risk factors that increase the probability that a parent will have a child with this disorder
Nondisjunction during either meiosis I or II can produce gametes with 2 copies of chromosome 21
Fusion with haploid gamete produces offspring with trisomy 21
Common because chromosome 21 is smaller and has less genes
Other trisomies with larger chromosomes are not viable
Risk factors of Down syndrome
Maternal age of 35 and older raises risk significantly
Average risk is 1/850, but rises to 1/10 with maternal age
Translocation Down syndrome
A parent with a Robertsonian translocation has an elevated risk of having a child with Down syndrome.
The production of unbalanced gametes can lead to trisomy 21
4% of individuals with Down syndrome have translocation Down syndrome
Be able to explain uniparental disomy and describe the molecular mechanisms leading to isodisomy and heterodisomy
Uniparental disomy
When an individual inherits both homologues from a single parent
Caused by nondisjunction events: one during meiosis, one during mitosis
Can occur for any chromosome
Isodisomy
Two copies of the same homologue from one parent
Can cause a child to inherit a recessive disorder from parent who is a carrier
Heterodisomy
One of each homologue from one parent
Understand how mitotic nondisjunction can lead to trisomic rescue
When a trisomic zygote undergoes mitosis, nondisjunction can eliminate the extra chromosome.
Uniparental disomy is observed if both homologues are from the same parent
If nondisjunction occurs after 1st mitotic division, individual may be a mosaic of disomic and trisomic cells.
Understand the different between recurring and sporadic chromosome syndromes and be able to describe examples of both classes of genetic disorders
Using clearly labeled drawings, be able to explain how NAHR between segmental duplications can lead to the duplication or deletion of genomic regions
Understand the molecular mechanisms underlying recurrent chromosome syndromes
NAHR at SDs
Key terms
Down syndrome
Translocation Down syndrome
Uniparental disomy
Isodisomy
Heterodisomy
Disomic rescue
Recurrent chromosome syndromes
Charcot-Marie Tooth Disease Type 1A (CMT1A)
Autosomal dominant peripheral neuropathy (defects in peripheral nervous system)
Progressive weakness and atrophy of leg muscles
Usually due to increased dosage of PMP22 gene on chromosome 17 (from 2 to 3 copies)
PMP22 encodes an integral membrane glycoprotein (peripheral myelin protein 22), required for myelin compaction in PNS.
Most patients are heterozygous for a tandem duplication of 1.5 Mb segment containing PMP22
Caused by reciprocal de novo mutations during meiosis
Hereditary neuropathy with liability to pressure palsies (HNPP)
Autosomal dominant demyelination disorder
Focal pressure neuropathies (numbness and tingling when pressure is applied)
Peroneal palsy with foot drop (paralysis on outside of calf)
Usually due to decreased dosage of PMP22 gene on chromosome 17 (from 2 copies to 1 —> haploinsufficiency)
Most patients heterozygous for deletion of 1.5 Mb segment containing PMP22.
Caused by reciprocal de novo mutations during meiosis
Segmental duplication
Long DNA sequences that are repeated in a genome
High level of sequence identity
Can cause deletions/duplications if paired accidentally
Contiguous gene syndromes
Due to changes in the dosage of multiple genes
Nonrecurrent (Idiopathic) chromosome syndrome
Cri du chat syndrome
Crying infant sounds like a meowing cat
Distinct facial appearance, variable levels of mental retardation, and speech defects
Most cases are due to haploinsufficiency of genes found in chromosome band 5p
Extent and breakpoints of deletions are highly variable
5p15 is a critical region missing in all patients
Deficiencies that extend proximally cause more severe intellectual impairment