Loss of CAA interruption and intergenerational CAG instability in Chinese patients with Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG expansions in huntingtin (HTT) gene, involving motor, cognitive, and neuropsychiatric symptoms. However, genetic modifiers and CAG repeat instability may lead to variations of clinical manifestations, making diagnosis of HD difficult. In this study, we recruited 229 HD individuals from 164 families carrying expanded CAG repeats of HTT, and analyzed loss of CAA interruption (LOI) on the expanded allele and CAG instability during germline transmission. Sanger sequencing and TA cloning were used to determine CAG repeat length and identify LOI variants. Detailed clinical features and genetic testing results were collected. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. In addition, we also presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. In conclusion, we present the first document of Asian HD population with LOI variant, and we suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice. KEY MESSAGES : We screened the loss of CAA interruption (LOI) variant in a Chinese HD cohort and presented the first document of Asian patients with Huntington's disease carrying LOI variant. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. We presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. We suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice.