Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China

Abstract Background Recent studies have reported that expanded GCA repeats in the GLS gene can cause glutaminase deficiency with ataxia phenotype. However, to data, no studies have investigated the distribution and role of GCA repeats in the GLS gene of Chinese individuals. Objective The aim was to investigate the distribution of GCA repeats in Chinese individuals, including undiagnosed ataxia patients for identifying causal factors, healthy controls for determining the normal range, and ATX− ATXN3 (spinocerebellar ataxia type 3, SCA3) patients for exploring genetic modifiers. Methods We combined whole‐genome sequencing (WGS), repeat‐primed polymerase chain reaction, capillary electrophoresis (RP−PCR/CE), and ExpansionHunter to screen the GCA repeats in the GLS gene of 349 undiagnosed ataxia individuals, 1505 healthy controls, and 1236 ATX− ATXN3 (SCA3) patients from mainland China. Results No expanded GCA repeats in the GLS gene were detected across any of the samples. The average number of GCA repeats was 11 (range: 8–31), 12 (range: 6–33), and 11 (range: 6–33) for undiagnosed ataxia patients, healthy controls, and SCA3 patients, respectively. The intermediate repeat size (9 < repeat size ≤ 13) of the nonexpanded GCA allele in the GLS gene was associated with later disease onset in ATX− ATXN3 (SCA3) patients. Conclusions Abnormal expansions of GLS GCA repeats are rare in the Chinese population. However, intermediate‐length normal GCA repeat sizes may influence the age at onset (AAO) in ATX‐ ATXN3 (SCA3) patients. © 2024 International Parkinson and Movement Disorder Society.