Frameshift and Copy Number Variants in SACS-Related Neuropathy

Autosomal recessive spastic ataxia of Charlevoix-Saguenay, caused by biallelic SACS variants, is classically characterized by spasticity, ataxia, and peripheral neuropathy. The aim of this study was to define the clinical and genetic spectrum of SACS-related inherited peripheral neuropathies (IPNs) in Japanese patients.

Targeted gene panel sequencing was performed in 3,353 Japanese cases clinically suspected of having IPN or Charcot-Marie-Tooth (CMT) disease, with PMP22 duplication or deletions pre-excluded in demyelinating subtypes, followed by whole-exome sequencing in a subset of undiagnosed cases. Depth-based copy number variation (CNV) analysis was conducted using CovCopCan or XHMM, with validation by quantitative PCR.

Biallelic or putative compound heterozygous SACS variants were identified in 10 index cases, with pathogenic or likely pathogenic variants confirmed in 9 cases (0.268%; 9/3,353). The variant spectrum included frameshift (n = 9), missense (n = 3), and nonsense (n = 2) variants, along with complete SACS gene deletions identified by CNV analysis in 2 cases. Disease onset occurred between 1 and 49 years. All patients exhibited motor and sensory neuropathy, with pyramidal signs observed in 6 patients. Cerebellar ataxia or atrophy was documented in 8 patients. Cognitive impairment was observed in 4 patients, and 1 patient presented with postural hypotension. Most patients showed a length-dependent, sensory-predominant polyneuropathy characterized by slowed nerve conduction velocities.

This study defines the contribution of SACS variants in a large case series of Japanese patients with IPN/CMT disease and delineates the heterogeneous genotypic and phenotypic spectrum of SACS-related neuropathies. The high frequency of gene-level deletions underscores the necessity of incorporating CNV analysis into the genetic diagnostic workflow for SACS-related disorders.