TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35

Yanxing Chen; Dengchang Wu; Benyan Luo; Guohua Zhao; Kang Wang

doi:10.1212/NXG.0000000000000424

TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35

Neurol Genet. 2020 Apr 22;6(3):e424. doi: 10.1212/NXG.0000000000000424. eCollection 2020 Jun.

Authors

Yanxing Chen¹, Dengchang Wu¹, Benyan Luo¹, Guohua Zhao¹, Kang Wang¹

Affiliation

¹ Department of Neurology (Y.C., G.Z.), the Second Affiliated Hospital, School of Medicine, Zhejiang University; and Department of Neurology (D.W., B.L., K.W.), the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Abstract

Objective: To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6.

Methods: Neurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype.

Results: The proband, presenting with myoclonic epilepsy, cognitive decline, and ataxia, harbored both the TGM6 p.L517W variant and expanded CAG repeats in gene ATN1. Further analysis of the other living family members in this pedigree revealed that the CAG repeat number was expanded in all the patients and within normal range in all the unaffected family members. However, the TGM6 p.L517W variant was absent in 2 affected family members, but present in 3 healthy individuals.

Conclusions: The nonsegregation of the TGM6 variant with phenotype does not support this variant as the disease-causing gene in this pedigree, questioning the pathogenicity of TGM6 in SCA35.