Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

Abstract

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

Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late‐onset ataxia

“…We identified pathological biallelic RFC1 expansions in 80% of cases with full‐blown CANVAS, in agreement with previous studies reporting at least 73% frequency in this subgroup, 3,8‐10 as well as in one case with sensory ataxic neuropathy. In the entire late‐onset ataxia cohort, the mutation hit rate was 6.5%, higher than one report, 6 similar to two previous studies, 7,8 but lower than the original cohort and one recent study 3,9,10 . Discrepancies between studies are likely to reflect stringency of inclusion criteria rather than true population differences.…”

“…Table 2 displays the frequency of biallelic pathological RFC1 expansions observed in late‐onset ataxia (all cases) versus incomplete CANVAS (cerebellar ataxia plus sensory neuropathy) vs. full‐blown CANVAS, and compares it to previous studies in ataxia cohorts 3,6‐10 . In our cohort, 4 out of 5 index cases (80%) with full‐blown CANVAS, 0 out of 10 index cases (0.0%) with incomplete CANVAS, and 5 out of 77 index cases (6.5%) with late‐onset ataxia carried biallelic pathological RFC1 expansions.…”

“…Biallelic pathological RFC1 expansions were originally identified in 92% of cases with full‐blown CANVAS, 54% of cases with cerebellar ataxia and sensory neuropathy, and 22% of late‐onset ataxias 3 . Recent studies have independently identified the biallelic pathological RFC1 expansion in ataxia cohorts, confirming very high frequency in patients with full‐blown CANVAS, but reporting lower rates in patients with incomplete CANVAS and late‐onset ataxia 6‐9 …”

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease

“…This high frequency rate of 14% may apply especially to populations with high consanguinity rates (50% in cohort B), while the prevalence of RFC1 disease in other populations could be closer to 1% to 4%, depending on the region and consanguinity rates. 16 , 17 Our results highlight that RFC1 disease is prevalent also in populations without central European origin such as Western Asian populations (Turkish populations, cohort B). Together with the identification of an Indonesian RFC1-family, with even severe disease course and premature death, these findings support the notion of RFC1 as a more global disease extending to Asia.…”

Neurology: Genetics Year in Review

“…The Fogel group at University of California at Los Angeles undertook a study to ascertain the prevalence of pathogenic repeat expansions in RFC1 and DAB1 in nearly 1,000 patients from North America with undiagnosed ataxia. Aboud Syriani and colleagues 1 examined almost 1,000 predominantly adult-onset and sporadic patients that had been excluded for repeat expansions in the SCA2, 3, 6, 7, and Friedreich ataxia genes. Patients were screened for the presence of pathogenic repeat expansions using fluorescent repeat-primed PCR (RP-PCR).…”