Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy

Abstract

The implementation of NGS methods into clinical practice allowed researchers effectively to establish the molecular cause of a disorder in cases of a genetically heterogeneous pathology. In cases of several potentially causative variants, we need additional analysis that can help in choosing a proper causative variant. In the current study, we described a family case of hereditary motor and sensory neuropathy (HMSN) type 1 (Charcot–Marie–Tooth disease). DNA analysis revealed two variants in the SH3TC2 gene (c.279G>A and c.1177+5G>A), as well as a previously described variant c.449−9C>T in the MPZ gene, in a heterozygous state. This family segregation study was incomplete because of the proband’s father's unavailability. To evaluate the variants’ pathogenicity, minigene splicing assay was carried out. This study showed no effect of the MPZ variant on splicing, but the c.1177+5G>A variant in the SH3TC2 gene leads to the retention of 122 nucleotides from intron 10 in the RNA sequence, causing a frameshift and an occurrence of a premature stop codon (NP_078853.2:p.Ala393GlyfsTer2).

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

“…In the current study, this variant was observed in two Russian families in a compound heterozygous state. In one family with two affected siblings the variant co-occurred with the variant c.1177 + 5G>A ( Shchagina et al, 2023 ) ClinVar: [VCV000575267.10]. In another unrelated proband, this variant was found in a compound heterozygous state with a novel single-nucleotide duplication c.3157dup (p. (Leu1053Profs*36)).…”

“…In another family (3514), the disease was caused by variants affecting splicing. c.1177 + 5G>A variant leads to the total absence of the normal transcript ( Shchagina et al, 2023 ). The c.279G>A variant has previously been shown to affect splicing, leading to the insertion of 19 nucleotides from intron 3 with the formation of a premature stop codon TAA in position 127 in the amino acid sequence ( Laššuthová et al, 2012 ).…”

A deep intronic variant inMMEcauses autosomal recessive Charcot-Marie-Tooth neuropathy through aberrant splicing

“…These variants typically lead to one or more mis-splicing events that result in the skipping of partial or complete exons, and/or the retention of partial or complete introns 21–42 . Pathogenic splicing variants have been found in several CMT genes including MPZ 21,30,39,40 , MFN2 22,30,31 , LRSAM1 23 , IGHMBP2 24 , INF2 25 , MCM3AP 26 , SH3TC2 30,32,38 , GDAP1 27,42 , SBF1 28 , NDRG1 37 , and FGD4 29 . Variants affecting canonical splice donor and acceptor sites have also been described in MME 4,41 .…”

Table1.XLSX

“…In another family (3514), the disease was caused by variants affecting splicing. c.1177 + 5G>A variant leads to the total absence of the normal transcript (Shchagina et al, 2023). The c.279G>A variant has previously been shown to affect splicing, leading to the insertion of 19 nucleotides from intron 3 with the formation of a premature stop codon TAA in position 127 in the amino acid sequence (Laššuthová et al, 2012).…”