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.
Highlights
The propositus presented with a severe demyelinating neuropathy confirmed by electromyography (Table 1)
Patients harboring two mutations in SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2) present with severe neuropathy of the peripheral nervous system characterized by important decrease in nerve conduction velocities (NCV), severe spine and foot deformities, and sometimes a cranial nerve involvement; symptoms usually appeared in the first decade of life [17,18]
The patient described in this paper presented a severe demyelinating neuropathy as well, associated with a motor and sensory disorder on the four limbs, severe foot deformities, and scoliosis since childhood, confirming the fact that the two detected mutations in SH3TC2 were certainly the cause of his disease
Summary
The diagnosis of inherited genetic diseases to which several causative genes have been associated is usually performed using the targeted next-generation sequencing (NGS) technique. A disease-specific gene panel is used to detect genomic mutations, improving the rate of patients getting positive diagnosis. To date, most of the detected mutations by targeted NGS are SNVs or small indels, but the SVs are often underdiagnosed. This is probably because few user-friendly tools (ExomeDepth, IonCopy, Cov’Cop, CovCopCan, DeviCNV) were available for geneticists to identify the SVs until recently and because these existing tools are maybe not systematically used in routine NGS analysis nowadays [1,2,3,4,5]
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