From Negative to Positive Diagnosis: Structural Variation Could Be the Second Mutation You Are Looking for in a Recessive Autosomal Gene

Abstract

Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. In Charcot–Marie–Tooth disease (CMT), the most common hereditary peripheral neuropathy, the PMP22-duplication was the first variation detected. Since then, more than 90 other genes have been associated with CMT, with point mutations or small indels mostly described. Herein, we present a personalized approach we performed to obtain a positive diagnosis of a patient suffering from demyelinating CMT. His NGS data were aligned to the human reference sequence but also studied using the CovCopCan software, designed to detect large CNVs. This approach allowed the detection of only one mutation in SH3TC2, the frequent p.Arg954*, while SH3TC2 is known to be responsible for autosomal recessive demyelinating CMT forms. Interestingly, by modifying the standard CovCopCan use, we detected the second mutation of this patient corresponding to a 922 bp deletion in SH3TC2 (Chr5:148,390,609-Chr5:148,389,687), including only one exon (exon 14). This highlights that SVs, different from PMP22 duplication, can be responsible for peripheral neuropathy and should be searched systematically. This approach could also be employed to improve the diagnosis of all inherited diseases.

Genetic Landscape of SH3TC2 variants in Russian patients with Charcot–Marie–Tooth disease

“…In addition, patients with both parallel and heterozygous mutations are accounted for differently in different studies. Large deletions have been described in the SH3TC2 gene (Cortese et al, 2020;Pyromali et al, 2022;Rehbein et al, 2023). In all cases, targeted searches for long deletions were carried out using various methods, including analysis of panel sequencing data and long-range PCR for target patients with specific clinical features of demyelinating polyneuropathies and one pathogenic variant in the SH3TC2 gene.…”

The First Large Deletion of ATL3 Identified in a Patient Presenting with a Sensory Polyneuropathy

“…Additionally, this type of recently developed software is not being employed systematically in routine analysis of NGS data. In order to improve patients’ diagnoses, we perform SV-research analysis in patients suffering from peripheral neuropathies using the CovCopCan software, and so far, we have detected pathogenic SVs in CMT patients [ 23 , 24 ] and in patients suffering from spastic ataxia of Charlevoix-Saguenay [ 17 ]. Moreover, SV research analysis has contributed to improving early diagnosis for patients presenting with inherited peripheral neuropathies [ 25 ].…”

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

“…Nonsense alterations in many CMT-associated genes result in a PTC, as has been previously shown in the GDAP1 gene, among others [ 4 ]. Nonsense mutations have been associated with both axonal and demyelinating forms of neuropathy [ 5 ]. Indeed, sequencing performed on 17,880 patients suffering from CMT associated with a panel of 14 genes, reported in the case of SH3TC2 a very high majority are nonsense mutations, some of which were found to be pathological [ 6 ].…”