Abstract
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited neuropathies. The GJB1 gene is the pathogenic gene of CMTX1. In this study, we screened a cohort of 465 unrelated Chinese CMT patients from years 2007 to 2019 and 650 controls by direct Sanger sequencing in GJB1 gene or targeted next-generation sequencing (NGS) or whole-exome sequencing (WES). A bidirectional Sanger sequencing would be performed on the 600 bases in the upstream promoter region and 30 bases in the 3′ untranslated region (UTR), if no mutation was found in the coding region of GJB1 of the patient. According to the results, 24 missense mutations, 4 nonsense mutation, 1 entire deletion, 1 intronic mutation, and 4 frameshift mutations in GJB1 were identified. Three of them were novel mutations (c.104 T>C, c.658-659 ins C, and c.811 del G). Moreover, central nervous system involvement was observed in five patients carrying mutations of R15W, V95M, R142W, R164W, and E186K. Our findings expand the mutational spectrum of the GJB1 gene in CMT patients. We also explored the genotype–phenotype correlation according to the collected information in this study. NGS panels for detecting inherited neuropathy should cover the non-coding region of GJB1.
Highlights
Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous inherited neuropathy [1], affecting ∼1 in 1,214 people in the world [2]
We found 34 different mutations in GJB1, including three that have not yet been reported
The frequency of GJB1 mutations was 9% in this cohort of CMT patients from mainland China, which is similar to studies in American and European countries [5, 13,14,15], as well as studies in Asian countries, such as Japan and Korea, and other studies in China [3, 16,17,18]
Summary
Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous inherited neuropathy [1], affecting ∼1 in 1,214 people in the world [2]. X-linked CMT (CMTX1) is the second most common form of CMT after CMT1A, accounting for 6.2% of all CMTs in the general population [2] and in 7–15% of all CMT patients in different patient cohorts [3,4,5]. It is caused by Gap junction protein beta-1 [GJB1, known as connexin 32 (Cx32)] gene mutations. More than 450 mutations have been identified to be related to GJB1 (hihg.med.miami.edu/code/http/cmt/public_html/index.html#/). Gross deletion, frameshift, and mutations in non-coding regions have been reported
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