One Multilocus Genomic Variation Is Responsible for a Severe Charcot-Marie-Tooth Axonal Form.

Federica Miressi,Franck Sturtz,Frédéric Favreau,Sylvie Bourthoumieux,Angélique Nizou,Paco Derouault,Pierre-Antoine Faye,Pascal Cintas,Anne-Sophie Lia,Corinne Magdelaine

doi:10.3390/brainsci10120986

Federica Miressi, Franck Sturtz + Show 8 more

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https://doi.org/10.3390/brainsci10120986

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Abstract

Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited disorders affecting the peripheral nervous system, with a prevalence of 1/2500. So far, mutations in more than 80 genes have been identified causing either demyelinating forms (CMT1) or axonal forms (CMT2). Consequentially, the genotype–phenotype correlation is not always easy to assess. Diagnosis could require multiple analysis before the correct causative mutation is detected. Moreover, it seems that approximately 5% of overall diagnoses for genetic diseases involves multiple genomic loci, although they are often underestimated or underreported. In particular, the combination of multiple variants is rarely described in CMT pathology and often neglected during the diagnostic process. Here, we present the complex genetic analysis of a family including two CMT cases with various severities. Interestingly, next generation sequencing (NGS) associated with Cov’Cop analysis, allowing structural variants (SV) detection, highlighted variations in MORC2 (microrchidia family CW-type zinc-finger 2) and AARS1 (alanyl-tRNA-synthetase) genes for one patient and an additional mutation in MFN2 (Mitofusin 2) in the more affected patient.

Highlights

Charcot–Marie–Tooth (CMT) disease, the most common peripheral neuropathy, is a hereditary disorder associated to numerous genomic mutations, which can occur in different genes and in different loci of the same gene
AARS1 duplication was confirmed by Array-Comparative Genomic Hybridization (aCGH) which allowed the identification of a 231 kb duplication, whose start and stop coordinates were identified in positions chr16:70185757 and chr16:70416579, respectively
Other genes were included in the detected duplication and they are listed in Supplementary Table S2

Summary

Introduction

Charcot–Marie–Tooth (CMT) disease, the most common peripheral neuropathy, is a hereditary disorder associated to numerous genomic mutations, which can occur in different genes and in different loci of the same gene. Posey et al showed, on a wild range of genetic pathologies, that phenotypical manifestations are the result of the combination of multiple genomic mutations in 4.9% of cases [1]. We describe here the genetic analysis of a family with two axonal CMT (CMT2) cases: Patient A (mother), characterized by axonal impairment, and patient B (daughter), with a more severe clinical. Brain Sci. 2020, 10, 986; doi:10.3390/brainsci10120986 www.mdpi.com/journal/brainsci. NGS analyses associated with Cov’Cop analysis, allowing the detection of structural variants (SV) [2], showed that both of them presented a known pathological mutation in MORC2. The more affected daughter had a third variation in MFN2 (Mitofusin 2)

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