Exploring THAP11 Repeat Expansion beyond Chinese‐Ancestry Cohorts: An Examination of 1000 Genomes and UK Biobank Data

Tan et al report novel CAG repeat expansion in THAP11 associated with spinocerebellar ataxia (SCA) in two Chinese families. They observed 45–100 repeats, three CAA interruptions, and a long uninterrupted 3' tail in sequencing of ataxic individuals from a single family.1 We investigated presence and size of THAP11 expansion in short-read next-generation sequencing of individuals with other ancestries in 1000 Genomes and the UK Biobank.2 Repeat genotypes of up to 50 triplets can be accurately typed with short read sequencing and bioinformatic tools.3 We genotyped CAG expansion in THAP11 (GRCh38 position chr16:67842863-67842950) with ExpansionHunter 5.0.0 and REViewer4 in 138 individuals with whole-genome sequencing in the UK Biobank2 and a history of hereditary ataxia or ataxia of unknown cause (ICD10 G110-G119; R270). We obtained THAP11 ExpansionHunter genotypes from 2504 unrelated individuals in 1000 Genomes.5 One European-ancestry ataxic individual in the UK Biobank has a 46/29 CAG THAP11 genotype, exceeding the proposed pathogenic threshold,1 and an uninterrupted 22-repeat CAG repeat expansion in CACNA1A that likely causes spinocerebellar ataxia type 6 (SCA6).6 REViewer visualization of ExpansionHunter genotyping shows six CAA interruptions to the THAP11 expansion (Fig. 1A) and no interruptions in the SCA6 expansion (Fig. 1B). The individual had primary care diagnoses of hereditary ataxia at 40, Parkinson's disease at 53, and received repeated prescriptions for trihexyphenidyl, a drug used in management of movement disorders. More-precise age of onset is not available as medical records in the UK Biobank are partial and participants are not re-contactable. THAP11 genotypes in the 1000 Genomes cohort were between 19 and 39 repeats. In the UK Biobank ataxia cohort, the range was 25 to 46 repeats. In both cohorts, the median was 29 repeats (IQR, 28–29) (Fig. 1C). We report the first finding of THAP11 CAG expansion in an ataxic individual of European ancestry. Interpretation of this expansion is complicated by detection of an uninterrupted pathogenic full-penetrance length SCA6 expansion and diagnosis of both ataxia and Parkinson's disease. This individual has six CAA interruptions, with nine uninterrupted 3′ repeats. We also provide length distributions of the THAP11 allele. Tan et al suggest toxicity of CAA-interrupted repeats based on CAG-pure sequences of ataxic individuals. They report one family where ataxic individuals with THAP11 expansion have three interruptions and 32 to 87 uninterrupted repeats in the 3′ end of the expansion, and unaffected family members have five to six interruptions and shorter tails. They also report THAP11 expansion in an unrelated individual (patient II-1), with six interruptions and 10 uninterrupted 3′ repeats (Tan et al's supporting information Figure S3),1 similar to our European-ancestry individual. Studies suggest CAA interruptions to CAG expansions stabilize intergenerational variability in repeat length,7 which may contribute to expansion instability in the family with fewer interruptions. Our findings show further work is necessary to elucidate the role of rare THAP11 expansion and its composition in ataxia and demonstrates that THAP11 expansion is detectable with bioinformatic approaches. It also further highlights the emerging complexity of expansion composition in tandem repeat-mediated disease. We thank Professor Paul Lockhart, Dr. Justin Read and Kayli Davies of the Murdoch Children's Research Institute, Melbourne, Australia for comments and feedback. This research was conducted with data from UK Biobank (www.ukbiobank.ac.uk), a major biomedical database, under data use agreement 36610 (PI Bahlo). This work was supported by the National Health and Medical Research Council (NHMRC) grants (GNT2001513, MRFF2007707 and MRFF2007677) to M.B., M.F.B. and H.R. H.R. was supported by a NHMRC Emerging Leadership 1 grant (1194364) and M.B. was supported by a NHMRC Leadership 1 grant (1195236). Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. L.G.F.: 1A, 1B, 1C, 2A, 2B, 3A, 3B; H.R. 1A, 2B, 2C, 3B; M.F.B. 1A, 2C, 3B; M.B. 1A, 1B, 2A, 2C, 3B. The data that support the findings of this study are available from the UK Biobank. Restrictions apply to the availability of UK Biobank data. Data from the Illumina Repeat Catalog are openly available at https://github.com/Illumina/RepeatCatalogs.