lect 30 Triplet Repeat Diseases: Huntington's and Fragile X

Flashcards covering the genetic basis, clinical characteristics, and diagnostic methods for Huntington's Disease and Fragile X Syndrome based on lecture notes.

Trinucleotide repeat disorders

Diseases resulting from an abnormal expansion of repetitive genomic sequences where a threshold number of repeats must be reached for clinical symptoms to appear.

Huntington's disease (HD)

A progressive neurodegenerative disorder with adult-onset (usually 30-40s) characterized by irritability, depression, poor coordination, cognitive decline, and chorea.

Chorea

Involuntary jerking or twitching movements associated with Huntington's disease.

HTT gene

Located on chromosome $4p16.3$, this gene spans $170\,kb$ with $67$ exons and is widely expressed for normal development.

Polyglutamine (poly Q) tract

An extended protein sequence in huntingtin resulting from the expansion of (CAG)n repeats in exon 1 of the $HTT$ gene.

Normal allele (HD)

A CAG repeat length of $<26$, where the diagnosis of HD is excluded.

Mutable normal allele (HD)

A CAG repeat length of $27-35$; the individual is normal, but there is a risk that offspring will develop HD.

Reduced penetrance allele (HD)

A CAG repeat length of $36-39$; the individual may or may not develop HD, and there is a risk for offspring.

Complete penetrance allele (HD)

A CAG repeat length of $\ge 40$, confirming the diagnosis of HD.

QF-PCR

Quantitative Fluorescent PCR used to diagnose CAG expansion in the $HTT$ gene by using a fluorescently labeled 5' primer and an unlabeled reverse primer.

Diagnostic Testing (Class I)

Standard testing performed for diagnostic purposes in a patient who already has symptoms to confirm the condition.

Predictive Testing (Class II)

Pre-symptomatic testing for individuals at an a priori $50\%$ or $25\%$ risk for late-onset conditions, requiring comprehensive genetic counseling and informed consent.

Fragile X syndrome (FXS)

An X-linked disorder (OMIM 300624) characterized by delayed speech, mental retardation, and methylation-induced loss of $FMR1$ transcription.

FMR1 gene

The gene involved in Fragile X syndrome, which undergoes transcriptional silencing due to (CGG)n expansion in its $5'UTR$.

Normal allele (FXS)

A repeat range of $5-44$ CGG repeats, ruling out the diagnosis of Fragile X syndrome.

Premutation (FXS)

A range of $55-200$ CGG repeats; the individual is a carrier at risk for primary ovarian insufficiency (POI) or ataxia (FXTAS).

Full mutation (FXS)

A repeat range of $>200-230$ CGG repeats, where the gene is methylated and inactive, confirming the diagnosis.

Methylation sensitive RFLP analysis

A method using Southern blotting and restriction enzymes to detect high copy number repeat sequences in FXS.

EcoR1

A restriction nuclease used in Southern blotting for FXS that cuts genomic DNA independently of its methylation status.

Eag1

A methylation-sensitive restriction enzyme that will not cut its recognition site if it is methylated.