Improved inherited peripheral neuropathy genetic diagnosis by whole‐exome sequencing

Abstract

Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype–phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.

EGR2 mutation enhances phenotype spectrum of Dejerine–Sottas syndrome

“…Inversely, the p.Arg409Trp mutation was reported to result a less severe phenotype than that of a patient with two mutations (p.Ser382Arg and p.Asp383Tyr) representing the most severe phenotype of the CHN [12]. EGR2 mutations may cause a variety of peripheral neuropathies [4]. Our case supports the hypothesis that EGR2 p.Arg359Trp results in early onset BSA phenotype with severe and rapid evolution.…”

BICD2 mutational analysis in hereditary spastic paraplegia and hereditary motor and sensory neuropathy

“…The observed lack of BICD2 mutations in HSMN patients is in line with the results of a recent study describing whole exome sequencing for 110 index patients with HMSN. Two novel heterozygous missense mutations, p.(Ala360Val) and p.(Val665Leu), were discovered, each in a single patient, but bioinformatics tools suggested that they may constitute rare variants rather than disease‐causing mutations . Overall, the interpretation of missense mutations still poses considerable challenges for genetic researchers and diagnostic specialists, and it has been estimated that even a considerable number of variants classified as disease‐causing in common databases may instead be rare variants …”

“…Further, because hereditary motor and sensory neuropathy (HMSN) may also show overlapping symptoms with SMALED, we investigated the presence of BICD2 mutations in a cohort of HMSN patients. To date, in one study performing whole exome sequencing in patients with HMSN, 2 previously unreported missense variants were described in the BICD2 gene, but bioinformatics analyses suggested these were most likely nonpathogenic variants …”

Diagnostic use of Massively Parallel Sequencing in Neuromuscular Diseases: Towards an Integrated Diagnosis

“…As an example, a variant in the Senataxin gene ( SETX ) reported as a putative mutation was finally confirmed as a non-pathogenic rare polymorphism [30]. Also, the implication of the gene in the pathology should be recognized, i.e.…”