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Pathogenicity threshold of spinocerebellar ataxia type 6 causative gene CACNA1A identified

March 5th, 2025

Pathogenicity threshold of SCA6 causative gene CACNA1A was identified — Relationship between age of onset and CAG repeat units of CACNA1A gene in patients with ataxia. Credit: Alteration of "Hatano Y, et al. *Neurology Genetics* 2024"

The Department of Neurology at Niigata University and the National Center of Neurology and Psychiatry (NCNP) have identified pathogenic thresholds for the CAG repeat units (RU) of the CACNA1A gene that causes spinocerebellar ataxia type 6 (SCA6). They investigated the SCA6 causative gene in 2,768 patients. They carefully examined the relationship between RU, age of onset, and family history.

The results of the study were published in the journal Neurology Genetics.

First, in cases with 18 or fewer RU, the proportion of family history was low. For 19 or more RU, the proportion of family history gradually increased and became almost constant at 23 or more RU. Next, based on the age of onset data for definitive SCA6 cases with 23 or more RU, they created a predictive curve for the relationship between RU and age of onset.

They found that over 90% of cases with 21 or more RU fell within the predicted age range. For cases with 19–20 RU, the proportion of cases within the predicted range decreased, and for cases with 18 or fewer RU, most cases fell outside the predicted range.

They evaluated the association between opposite alleles and age of onset using multiple regression analysis. The results showed that for cases with expanded alleles of 21 and 22 RU, opposite alleles were associated with age of onset.

For cases with expanded alleles of 23 RU or more, no association was found between opposite alleles and age of onset. Additionally, cases with expanded alleles of 19-20 RU had a significantly higher proportion of opposite alleles of 19 or more compared to cases with expanded alleles of 23 RU or more.

"When examining ataxia patients with 21RU or more, it is reasonable to consider SCA6. However, for patients with 19-20 RU, careful consideration is necessary to determine if it is SCA6. When the OA is also 19-20 RU, the probability of having SCA6 increases. Our findings may have important implications for SCA6 diagnosis and genetic counseling," explains Dr. Hatano and Dr. Ishihara.

More information:
Yuya Hatano et al, Redefining the Pathogenic CAG Repeat Units Threshold in CACNA1A for Spinocerebellar Ataxia Type 6, Neurology Genetics (2025). DOI: 10.1212/NXG.0000000000200245

Provided by Niigata University

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