HTT CAG Repeat Length Variation in Huntington Disease (HD) Patients: Experience from a US Reference Laboratory
Sat Dev Batish1, Marc Meservey1, Farnoosh Haji-Sheikhi2, Elise Nedzweckas1, Zhenyuan Wang1, Vivekananda Datta2, Thomas Mullen2, Jeff Radcliff2
1Athena Diagnostics, 2Quest Diagnostics

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

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.   

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.

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.
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.