Huntington’s disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of an unstable CAG repeat sequence in the Huntingtin (HTT) gene. The prevalence of HD, allelic diversity, rate of novel expansions and the clinical correlates vary across populations.

We analyzed the diversity of alleles and their clinical correlates and examined the inheritance patterns and the pattern of instability of CAG repeats in a few families.

Clinical history and pedigree structure were collected from records or through interviews between 2016 and 2019. Genetic testing at the HD locus was done on clinical suspicion, or relatedness, after counseling. Descriptive statistics and correlation analysis were used.

Expanded repeats were detected in 239 individuals, including 232 who were symptomatic and 7 presymptomatic relatives. The number of CAG repeats (mean = 45.6) and age at onset (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 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, with de novo expansion confirmed in three cases.

Novel mutations at the HTT locus may not be rare in India. A lack of family history should not exclude appropriate testing. The prevalence of IA and incidence of de novo expansions suggest that there may be a reservoir of alleles prone to expansion.

Intracranial aneurysm (IA) is an expansion of the weakened arterial wall that is often asymptomatic until rupture, resulting in subarachnoid hemorrhage. Here we describe the high prevalence of familial IA in a cohort of Newfoundland ancestry. We began to investigate the genetic etiology of IA in affected family members, as the inheritance of this disease is poorly understood.

Whole exome sequencing was completed for a cohort of 12 affected individuals from two multiplex families with a strong family history of IA. A filtering strategy was implemented to identify rare, shared variants. Filtered variants were prioritized based on validation by Sanger sequencing and segregation within the families.

In family R1352, six variants passed filtering; while in family R1256, 68 variants remained, so further filtering was pursued. Following validation by Sanger sequencing, top candidates were investigated in a set of population controls, namely, C4orf6 c.A1G (p.M1V) and SPDYE4c.C103T (p.P35S). Neither was detected in 100 Newfoundland control samples.

Rare and potentially deleterious variants were identified in both families, though incomplete segregation was identified for all filtered variants. Alternate methods of variant prioritization and broader considerations regarding the interplay of genetic and environmental factors are necessary in future studies of this disease.