Prevalence of -mediated spinocerebellar ataxia in a North American ataxia cohort.

Objective: We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 () and disabled adaptor protein 1 in an undiagnosed ataxia cohort from North America.

Methods: A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in (AAGGG) and (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for , resulting in a combined 911 subjects tested.

Results: In the initial cohort, 41 samples were identified with 1 expanded allele in the gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the gene (spinocerebellar ataxia type 37).

Conclusions: In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.