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Walk Neuropathy Research and Education fund"},{"DOI":"10.13039\/100007249","name":"University of Minnesota Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007249","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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).<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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\u2019s 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&amp;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 (\u0394CMTES) = 1.3 \u00b1 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\u20137; 3-year \u0394CMTES = 2.3 \u00b1 2.5, P = 0.001, SRM = 0.90).<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awad187","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T12:27:08Z","timestamp":1686140828000},"page":"4336-4349","source":"Crossref","is-referenced-by-count":38,"title":["Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to\n                    <i>GJB1<\/i>\n                    variants"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9802-2683","authenticated-orcid":false,"given":"Christopher J","family":"Record","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London, WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariola","family":"Skorupinska","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London, WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde","family":"Laura","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London, WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M","family":"Rossor","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London, WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-765X","authenticated-orcid":false,"given":"Davide","family":"Pareyson","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta , 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3850-076X","authenticated-orcid":false,"given":"Chiara","family":"Pisciotta","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta , 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawna M E","family":"Feely","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Iowa Carver College of Medicine , Iowa City, IA 52242 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Neuroscience, John Hopkins University School of Medicine , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-170X","authenticated-orcid":false,"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0PY , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Sadjadi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester , Rochester, NY 14618 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Houston Methodist Hospital , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Walk","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Minnesota , Minneapolis, MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina W","family":"Yum","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"},{"name":"Department of Neurology, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cedars-Sinai Medical Center , Los Angeles, CA 90048 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Neurology, Stanford University , Stanford, CA 94304 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Burns","sequence":"additional","affiliation":[{"name":"University of Sydney School of Health Sciences, Faculty of Medicine and Health; 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