A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease

Abstract

Background Charcot–Marie–Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X‐linked CMT disease. Methods In this study, the probands and his mother underwent electrophysiological examinations and other family members were assessed retrospectively. Whole‐exome sequencing, Sanger sequencing, and SNP array linkage analysis were performed to find and confirm the variant. The functional effect of the identified variant was further investigated in HEK293 cells and MCF‐7 cells by minigene splicing assay. Results The affected individuals had some clinical symptoms including symmetric atrophy and progressive weakness of the distal muscles in their twenties. Electrophysiological examinations result in peripheral nerve injury of the upper and lower limbs. Whole‐exome sequencing identified a novel hemizygous deletion mutation (NM_000166: c.‐16‐8_‐14del) in the GJB1 gene. SNP array linkage analysis and co‐segregation analysis confirmed this mutation. Minigene splicing assay verified that this mutation leads to the activation of cryptic splicing sites in exon 2 which results in the deletion of exon 2. Conclusion Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

A deep intronic variant in MME causes autosomal recessive Charcot–Marie–Tooth neuropathy through aberrant splicing

“…Splice‐altering variants can weaken or abolish recognition of the correct splice sites, or alternatively strengthen or create cryptic splice sites that mimic consensus splicing sequences 20 . 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 .…”