Are rare coding mutations in the genes related to genetic peripheral neuropathies risk factors in multiple sclerosis (MS)

Introduction: MS is chronic inflammatory disease of the central nervous system with important genetic contribution. Although familial contribution to MS etiology is well established, much of genetic contribution still remains poorly defined. Several case reports reported comorbidity between different types of genetic peripheral neuropathies and MS. Therefore we hypothesized that there is an increased mutation burden in genes related to peripheral neuropathies among MS patients. Materials and Methods: Whole exome sequencing using Nextera Coding Exome enrichment was performed in 48 patients with familial MS, 40 patients with sporadic MS and 92 population- matched controls. Genotypes were called using GATK toolkit in multisample mode and only sites with variant quality over 100.0 and genotyping rate of over 60% across all samples were kept in downstream analyses. The selection of variants among bioinformatically focused panel of 52 peripheral neuropathy related genes was narrowed in accordance of functional impact predicted by snpEff - all truncating variants and missense variants predicted as pathogenic by a majority of in-silico predictors, were considered in further burden analyses. Results: We identified 8 candidate genetic variants (7 genes) that affect function in familial MS, and 11 candidate genetic variants (12 genes) in sporadic MS patients. Overall we detected a statistically significant 1.9-times enrichment of mutations (p=0.004) in the familial MS cases compared to the ExAC control samples. Conclusions: Exome sequencing of peripheral neuropathy causing genes revealed an excess burden of deleterious coding variants in familial MS patients which supports previous evidence of comorbidity among peripheral neuropathies and MS.