A National French Consensus on Gene List for the Diagnosis of Charcot-Marie-Tooth Disease and Related Disorders Using Next-Generation Sequencing.

Thibaut Benquey,Shahram Attarian,Martin Krahn,Anne-Sophie Lia,Bruno Francou,Marie-Claire Malinge,Philippe Latour,Aurélien Perrin,Annamaria Molon,Anne Guiochon-Mantel,Nathalie Bonello-Palot,Corinne Magdelaine,Eric Leguern,Nicolas Lévy,Mathieu Cerino,Emmanuelle Pion,Mireille Cossée,Tanya Stojkovic

doi:10.3390/genes13020318

Abstract

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of gene panels exists at national and international levels. Here, we present the work of the French National Network for Rare Neuromuscular Diseases (FILNEMUS) genetic diagnosis section which coordinates the seven French diagnosis laboratories using NGS for peripheral neuropathies. This work aimed to establish a unique, simple and accurate gene classification based on literature evidence. In NSIPN, three subgroups were usually distinguished: (1) HMSN, Hereditary Motor Sensory Neuropathy, (2) dHMN, distal Hereditary Motor Neuropathy, and (3) HSAN, Hereditary Sensory Autonomic Neuropathy. First, we reported ClinGen evaluation, and second, for the genes not evaluated yet by ClinGen, we classified them as “definitive” if reported in at least two clinical publications and associated with one report of functional evidence, or “limited” otherwise. In total, we report a unique consensus gene list for NSIPN including the three subgroups with 93 genes definitive and 34 limited, which is a good rate for our gene’s panel for molecular diagnostic use.

Highlights

The FILNEMUS consortium was a real springboard for the seven French neuropathy diagnostic laboratories using the Next generation sequencing (NGS) approach for non-syndromic inherited peripheral neuropathies (NSIPN)
127 genes were classified into NSIPN; 81 genes reported in Hereditary Motor and SensoryNeuropathies (HMSN), 26 in distal Hereditary MotorNeuropathies (dHMN), and 20 in Hereditary Sensory Autonomic Neuropathies (HSAN) (Table 1) with overlap between the different subgroups
TRPV4 is reported in Charcot–Marie–Tooth disease (CMT) and dHMN, SCN9A in HSAN and congenital insensitivity and more

Summary

Introduction

Charcot–Marie–Tooth disease (CMT) encompasses Hereditary Motor and Sensory. They represent the most frequent inherited peripheral neuropathy. Related disorders with overlapping clinical findings include distal Hereditary Motor. Neuropathies (dHMN), Hereditary Sensory Autonomic Neuropathies (HSAN), among others. Termed non-syndromic inherited peripheral neuropathies (NSIPN) in this article, these disorders represent the most common group of inherited neuromuscular diseases with an estimated prevalence of 1 in 2500 [1]. Over the past 30 years, a huge revolution in molecular genetics and genomics has occurred.

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