Whole-Genome and Long-Read Sequencing Identify a Novel Mechanism in Resulting in CANVAS Syndrome.

Objectives: Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) results from biallelic intronic pentanucleotide repeats in We describe an adult male proband with progressive imbalance, cerebellar atrophy, somatosensory neuronopathy, and absence of peripheral vestibular function for whom clinical testing demonstrated a heterozygous expansion consistent with an unaffected carrier.

Methods: We performed whole-genome sequencing (WGS) on peripheral blood DNA samples from the proband and his unaffected mother. We performed DNA long-read sequencing and synthesized complementary DNA from RNA using peripheral blood from the proband.

Results: WGS confirmed the maternally inherited expansion and identified a rare, nonsense variant: c.C1147T; p.R383X in the proband but not the maternal DNA sample. variants were confirmed in with long-read sequencing. Functional studies demonstrated the absence of complementary DNA (cDNA) transcript from the c.C1147T; p.R383X variant supporting nonsense-mediated decay of this transcript.

Discussion: We report an adult with CANVAS due to compound heterozygous pathogenic variants: the pathogenic intronic pentanucleotide expansion confirmed in with a nonsense variant. This report represents a novel molecular mechanism for CANVAS. Sequencing for should be considered for adults meeting clinical criteria for the CANVAS phenotype if only a heterozygous pathogenic expansion is identified.