Abstract Details

Title HTT CAG Repeat Length Variation in Huntington Disease (HD) Patients: Experience from a US Reference Laboratory

Topic General Neurology

Presentation(s) General Neurology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 007

Objective

To assess the variations in CAG repeat length in HTT, the gene associated with HD.

Background HD is a dominantly inherited neurodegenerative disorder characterized by expansion of the CAG repeat in HTT. Age at onset varies widely, averaging 40 years. CAG repeat length in HTT shows a strong negative correlation with age at symptom onset. To assess this relationship in a nationally representative group of patients with presumed HD symptoms, we analyzed CAG repeat number by age in specimens submitted to Athena (Quest) Diagnostics for HTT testing. To our knowledge, this is the largest such study to date based on real-world data from a reference laboratory.

Design/Methods

A convenience sample of results from specimens consecutively submitted for HTT analysis (to confirm HD diagnosis) was selected. CAG repeat expansions were analyzed by PCR, and by Southern blotting for juvenile homozygous cases. Age at testing was presumed to reflect age at symptom onset. The association between CAG repeats and onset age was examined using polynomial regression.

Results 26,037 specimens were included, representing 5 age groups: <18 years (3.4%), 18-30 (10.1%), 31-50 (33.9%), 51-70 (39%), and >70 (13.6%). Of these specimens, 11,390 (43.7%) had CAG repeat lengths consistent with HD–including 605 with reduced penetrance alleles and 34 with expansions on both alleles. Repeat lengths of 40-45 were the most common (72.8%), followed by 46-50 (15.9%). The distribution of repeat lengths was negatively associated with onset age (P<0.001). Repeat lengths >70 were more common in patients <18 years old (n=58; 35.1%) than in older patients (n=7; 0.06%) (P<0.001); almost all (5649/5650; 99.9%) patients older than >50 at onset had repeat lengths ≤50.

Conclusions The most common pathogenic HD alleles have repeat lengths in the 40-50 range. Longer expansions are rare in patients older than 50 at onset but common in those <18.

Authors/Disclosures
Sat Dev Batish, PhD, FAAN (Athena Diagnostics) PRESENTER	Dr. Batish has received stock or an ownership interest from Quest Diagnostics.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Zhenyuan Wang, PhD (Athena Diagnostics)	Dr. Wang has nothing to disclose.
Vivekananda Datta	Vivekananda Datta has received personal compensation for serving as an employee of Quest Diagnostics.
Thomas E. Mullen, PhD (Quest Diagnostics)	Dr. Mullen has received personal compensation for serving as an employee of Quest Diagnostics. Dr. Mullen has received stock or an ownership interest from Quest Diagnostics.
	No disclosure on file

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