Lecture 4

Learning Outcomes

1. 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

2. 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).

3. 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

4. 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

5. 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.

6. Understand the different between recurring and sporadic chromosome syndromes and be able to describe examples of both classes of genetic disorders

7. Using clearly labeled drawings, be able to explain how NAHR between segmental duplications can lead to the duplication or deletion of genomic regions

8. 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