A significant inflation in TGM6 genetic risk casts doubt in its causation in spinocerebellar ataxia type 35.

Spinocerebellar ataxia 35 (SCA35) has been associated with pathogenic mutations in the gene TGM6. In a Chinese exome sequencing cohort, we identified 8 families with reported TGM6 variants sharing no features of SCA35. Considering this finding, we reviewed the public database gnomAD and found these variants to be significantly more common in the East Asians than in other ethnic groups (P < 0.0001). Gene constraint metrics showed that both missense and loss-of-function variants in TGM6 are likely to be tolerated and there is no regional constraint. By performing inflation analysis, it demonstrated that the cumulative frequency of TGM6 reported pathogenic variants is at least 111-fold inflated over disease prevalence of all autosomal dominant SCAs, indicating a high chance of misdiagnosis or low penetrance. Misclassification of benign or low penetrant variants as pathogenic is a significant problem that often results in genetic misdiagnosis. This highlights the necessity of evaluating variant pathogenicity with sequencing of genomes from diverse populations, both from asymptomatic controls and phenotypically different patients, in order to ensure accurate classification of variants.