An 8-generation family with X-linked Charcot–Marie–Tooth: Confirmation Of the pathogenicity Of a 3′ untranslated region mutation in GJB1 and its clinical features

Introduction: Mutations in gap junction protein beta 1 (GJB1) on the X chromosome represent one of the most common causes of hereditary neuropathy. We assessed manifestations associated with a rare 3′ untranslated region mutation (UTR) of GJB1 in a large family with X-linked Charcot–Marie–Tooth disease (CMTX). Methods: Clinical, electrophysiological, and molecular genetic analyses were performed on an 8-generation family with CMTX. Results: There were 22 affected males and 19 symptomatic females, including an 83-year-old woman followed for 40 years. Electrophysiological studies showed a primarily axonal neuropathy. The c.*15C>T mutation in the GJB1 3′ UTR was identified in 4 branches of the family with a log of odds (LOD) of 4.91. This created a BstE II enzyme recognition site that enabled detection by restriction digestion. Discussion: The c.*15C>T mutation in the GJB1 3′ UTR segregates with CMTX1 in 8 generations. Penetrance in males and females is essentially complete. A straightforward genetic method to detect this mutation is described. Muscle Nerve 57: 859–862, 2018.