Allelic Diversity, de novo CAG Expansions, and Intergenerational Instability at the HTT Locus in a clinical sample of Huntingtons Disease from India

BACKGROUNDHuntingtons disease (HD) is an inherited, neurodegenerative disorder, caused by the expansion of an unstable CAG repeat sequence in the HTT gene. The prevalence of HD, allelic diversity, rate of novel expansions, and the clinical correlates, vary across populations. OBJECTIVEWe aimed to analyze the diversity of alleles, and their clinical correlates; and describe the mode of inheritance and the pattern of instability of CAG repeats in a few families METHODSClinical history and pedigree structure were collected from clinical records, or through interviews between 2016-19. Genetic testing at the HD locus was done on clinical suspicion, or relatedness, after counseling. Descriptive statistics and correlation analysis were used. RESULTSExpanded repeats were detected in 239 individuals, including 232 who were symptomatic, and seven presymptomatic relatives. The number of CAG repeats (mean=45.6) and age at onset (AAO) (mean=39.2 years) showed a strong inverse correlation (r=-0.67). We found atypical alleles such as 8 intermediate alleles (IA), 12 reduced penetrance alleles (RPA) and 14 large (>60) expansion alleles corresponding to juvenile HD. Three individuals carried biallelic expansions. Paternal inheritance was more common and the mean increase in repeats in the available parent-child pairs was 14. Thirty-seven individuals had no family history of HD, of which a de novo expansion could be ascertained in 3 cases. CONCLUSIONSNovel mutations at HTT locus may not be rare in India. A lack of family history should not exclude appropriate testing. Prevalence of intermediate alleles and incidence of de novo expansions, suggests that there may be a reservoir of alleles prone to expansion.