Prevalence of <i>RFC1</i> -mediated spinocerebellar ataxia in a North American ataxia cohort

Abstract

<h3>Objective</h3> We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (<i>RFC1</i>) and disabled adaptor protein 1 <i>(DAB1)</i> in an undiagnosed ataxia cohort from North America. <h3>Methods</h3> 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 <i>RFC1</i> (AAGGG) and <i>DAB1</i> (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 <i>RFC1</i>, resulting in a combined 911 subjects tested. <h3>Results</h3> In the initial cohort, 41 samples were identified with 1 expanded allele in the <i>RFC1</i> 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 <i>RFC1</i> (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 <i>DAB1</i> gene (spinocerebellar ataxia type 37). <h3>Conclusions</h3> In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in <i>RFC1</i> was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.