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

• Main Authors: Federica Miressi, Corinne Magdelaine, Pascal Cintas, Sylvie Bourthoumieux, Angélique Nizou, Paco Derouault, Frédéric Favreau, Franck Sturtz, Pierre-Antoine Faye, Anne-Sophie Lia
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Brain Sciences
• Subjects: multilocus disease; Charcot–Marie–Tooth; diagnosis; CNV; NGS
• Online Access: https://www.mdpi.com/2076-3425/10/12/986

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 <i>MORC2</i> (microrchidia family CW-type zinc-finger 2) and <i>AARS1</i> (alanyl-tRNA-synthetase) genes for one patient and an additional mutation in <i>MFN2</i> (Mitofusin 2) in the more affected patient.