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

3 0 repeats


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

Results
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). 6REViewer 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.

Discussion
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 0 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 0 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 0 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 repeatmediated disease.was found beyond Chinese ataxia population.Therefore, this patient further confirmed this new subtype of spinocerebellar ataxia (SCA).In addition, Fearnley et al also investigated the normal expansion ranging from 19 to 39 repeats in THAP11 from 2504 individuals in 1000 Genomes.In general, these findings suggest that ATX-THAP11 is not limited to Asian.As the latest SCA included in Online Mendelian Inheritance in Man (OMIM) is SCA50, the new SCA subtype caused by the CAG expansion in THAP11 identified by us is appropriately named ATX-THAP11/SCA51.
The pathogenic mechanism of polyQ diseases is widely attributed to the toxicity of abnormal proteins containing stretches of polyQ residues. 1We observed an increase in the length of glutamine correlates with a more severe phenotype in our ATX-THAP11/SCA51 family. 2 Interestingly, expansion of CAG repeats interrupted by CAA is common in polyQ disease, which encodes the same glutamine for polyQ stretch, but may lead to distinct RNA secondary structures. 1 In recent years, several reports have explored the impact of various DNA structures within CAG repeats on the severity of polyQ diseases.Three independent studies have reported that in individuals with Huntington's disease (HD), a reduction in CAA insertions and an increase in uninterrupted CAG repeats are associated with an earlier onset age of HD. 3,4 Conversely, increased CAA insertions are linked to delayed disease onset. 3urther comparisons among different HD mouse models have demonstrated that longer uninterrupted CAG repeats are associated with striatum-selective transcriptionopathy, possibly because of CAG repeat instability and nuclear aggregation. 5Another intriguing observation is that pure CAG repeats in ATXN2 are associated with SCA2, whereas CAG repeats in ATXN2 causing amyotrophic lateral sclerosis (ALS) and Parkinson's disease are predominantly interrupted by CAA. 6 In Drosophila models, ataxin-2 encoded by pure CAG repeats induces retinal and neurotoxicity, whereas CAA insertions or only CAA repeats do not induce toxicity, despite producing the same protein. 7In our large family affected by ATX-THAP11/SCA51, we noted a decrease in CAA insertions and an increase in pure CAG length.However, there was no decrease in CAA insertions in our other family or in the patient reported by Fearnley et al.Currently, because of the limited number of ATX-THAP11/SCA51 patients, whether CAA interruption modulates pathogenesis of polyQ aggregation and influences clinical phenotypes needs further exploration.
In the future, it is necessary to detect CAG repeat expansion of THAP11 across ethnically and geographically different ataxia populations to clarify its genotype-phenotype characteristics and pathogenesis of ATX-THAP11/SCA51.
Fearnley et al reported an ataxia case with a 46 of 29 CAG repeats in THAP11, comorbid with a 22-CAG repeat expansion in CACNA1A from European-ancestry ataxia cohort.This patient was diagnosed as hereditary ataxia at the age of 40 and Parkinson's disease at 53.The comorbidity of two polyglutamine (polyQ) diseases may complicate the phenotype and further assessment is warranted.Nevertheless, this is the first time that CAG expansion greater than 45 repeats in THAP11