Week 9 Part 1 - Laboratory Diagnosis of Huntington Disease

Question 1

Huntington Disease (HD)

Answer 1

Progressive neurodegenerative disorder -> dementia
- presents with movement disorder, cognitive impairment and psychiatric disturbances
Symptoms usually manifest between 35 & 50 years
Pathologically by loss of specific neuronal populations
- general shrinkage of the brain and degeneration of caudate and striatum cells and less severe loss in the cerebral cortex

Question 2

Genomic Abnormality in Huntington’s Disease

Answer 2

Instability of CAG repeat length in sperm and oocyte DNA

Question 3

HD Special Populations

Answer 3

Juvenile HD is defined as <20 y; sub- categories:
- early infantile onset < 10 years old
- juvenile onset < 20 years old

Question 4

HD Pathogenic Mutation

Answer 4

New pathogenic mutation & homozygous expansions are rare
Homozygous is defined as individuals with >36 CAG repeats in both alleles
Term biallelic HD (B-HD) has been used to describe individuals with 1 mutated allele (≥40 CAG repeats) & the other CAG expanded allele (≥27)

Question 5

Huntington Gene

Answer 5

On chromosome 4p16.3, spans 170 kb with 67 exons
HTT gene is widely expressed & is required for normal development
HD due to expansion of unstable polymorphic trinucleotide (CAG)n repeat in exon 1 of the HTT gene, which translates into an extended polyglutamine tract in the Huntington gene

Question 6

International Guidelines for Classification of Huntington Disease Status

Answer 6

Normal allele
- CAG repeat: ≤26
- phenotype: normal
Mutable normal allele
- CAG repeat: 27-35
- phenotype: normal
HD allele
- CAG repeat: 36-39
- phenotype: HD (may have reduced penetrance, may not develop HD)
HD allele
- CAG repeat: ≥40
- phenotype: HD

Question 7

Allele Sizes

Answer 7

Mutable normal alleles 27-35 CAG repeats
- alleles can be unstable in sperm
- pathologic expansion of paternally derived alleles
HD alleles with reduced penetrance 36-39 CAG repeats
- rare cases, alleles in this range found in elderly asymptomatic individuals >70 years
HD alleles with full penetrance ≥40 CAG repeats
- no reports of the absence of HD pathology in any individual with ≥40 CAG repeats

Question 8

Types of Testing for HD

Answer 8

Presymptomatic
- requested on individuals at an a priori 50 or 25% risk
Diagnostic
Prenatal testing
- CVS
- exclusion
Preimplantation genetic diagnosis (PGD)

Question 9

What is Preimplantation genetic diagnosis (PGD)

Answer 9

Technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder
It is used to detect genetic changes in embryos that were created using IVF

Question 10

Genetic Testing on Embryos

Answer 10

PGT-A - testing for aneuploidy, presence of an extra chromosome
PGT-M - testing for monogenic and single gene disorders.
PGT-SR - testing for structural chromosomal rearrangements

Question 11

HD PCR

Answer 11

Question 12

Counselling Issues

Answer 12

Timing of patient presentation
- burden of uncertainty ~75%
- reproductive issues ~10%
- for sake of children ~15%
Outcome of counselling
- ncreased q%
- ncreased sleep / relationship issues ~15%
- qSaviour Syndrome