Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants
Authors: Record Christopher J , Skorupinska Mariola , Laura Matilde , Rossor Alexander M , Pareyson Davide , Pisciotta Chiara , Feely Shawna M E , Lloyd Thomas E , Horvath Rita , Sadjadi Reza , Herrmann David N , Li Jun , Walk David , Yum Sabrina W , Lewis Richard A , Day John , Burns Joshua , Finkel Richard S , Saporta Mario A , Ramchandren Sindhu , Weiss Michael D , Acsadi Gyula , Fridman Vera , Muntoni Francesco , Poh Roy , Polke James M , Zuchner Stephan , Shy Michael E , Scherer Steven S , Reilly Mary M ,   for the Inherited Neuropathies Consortium—Rare Disease Clinical Research Network, Abreu Lisa , Anderson Kimberly A , Baratta Silvia , Berry Debbie , Blake Julian , Cavalca Eleonora , Cornett Kayla , Cortese Andrea , Donlevy Gabrielle , Dragon Amanda , Dudziec Magdalena , Estilow Katy Eichinger Tim , Ferment Valerie , Grant Natalie , Grider Tiffany , Hyslop Emily , Jones Tara , Kressin Nicole , Leon Wendy , Magri Stefania , McCray Brett , Menezes Manoj , Milev Evelin , Parrott Lindsey , Patel Pooja , Pires Cláudia Brito , Prada Valeria , Ramdharry Gita , Saveri Paola , Schirinzi Giulia , Shy Rosemary , Siskind Carly , Sowden Janet , Stork Sydney , Sumner Charlotte J , Taroni Franco , Thomas Simone , Twachtman-Bassett Jennifer , Villalpando Nidia , Vujovic Dragan , Wells Julie , Wood Elizabeth , Zuccarino Riccardo 
Published: June 2023

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS).

In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS.

We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar’s classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G&gt;A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0–7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90).

Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.