Mariëlle Wohlgemuth1, Richard J Lemmers1, Marianne Jonker1, Elly van der Kooi1, Corinne G Horlings1, Baziel G van Engelen1, Silvere M van der Maarel1, George W Padberg1, Nicol C Voermans2. 1. From the Department of Neurology (M.W., C.G.H., B.G.v.E., G.W.P., N.C.V.), Donders Institute for Brain, Cognition and Behavior, and Radboud Institute for Health Sciences (M.J.), Radboud University Medical Center, Nijmegen; Department of Neurology (M.W.), ETZ, Tilburg; Department of Human Genetics (R.J.L., S.M.v.d.M.), Leiden University Medical Center; and Department of Neurology (E.v.d.K.), MCL, Leeuwarden, the Netherlands. 2. From the Department of Neurology (M.W., C.G.H., B.G.v.E., G.W.P., N.C.V.), Donders Institute for Brain, Cognition and Behavior, and Radboud Institute for Health Sciences (M.J.), Radboud University Medical Center, Nijmegen; Department of Neurology (M.W.), ETZ, Tilburg; Department of Human Genetics (R.J.L., S.M.v.d.M.), Leiden University Medical Center; and Department of Neurology (E.v.d.K.), MCL, Leeuwarden, the Netherlands. nicol.voermans@radboudumc.nl.
Abstract
OBJECTIVE: An observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype-genotype correlations. METHODS: Ten FSHD1 probands carrying 4-9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels. RESULTS: The maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats. DISCUSSION: This family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling.
OBJECTIVE: An observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype-genotype correlations. METHODS: Ten FSHD1 probands carrying 4-9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels. RESULTS: The maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats. DISCUSSION: This family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling.
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Authors: Sabrina Sacconi; Audrey Briand-Suleau; Marilyn Gros; Christian Baudoin; Richard J L F Lemmers; Sophie Rondeau; Nadira Lagha; Pilvi Nigumann; Chiara Cambieri; Angela Puma; Françoise Chapon; Tanya Stojkovic; Christophe Vial; Françoise Bouhour; Michelangelo Cao; Elena Pegoraro; Philippe Petiot; Anthony Behin; Bras Marc; Bruno Eymard; Andoni Echaniz-Laguna; Pascal Laforet; Leonardo Salviati; Marc Jeanpierre; Gaël Cristofari; Silvère M van der Maarel Journal: Neurology Date: 2019-04-12 Impact factor: 9.910
Authors: Sanne C C Vincenten; Nienke Van Der Stoep; Aimée D C Paulussen; Karlien Mul; Umesh A Badrising; Marjolein Kriek; Olivier W H Van Der Heijden; Baziel G M Van Engelen; Nicol C Voermans; Christine E M De Die-Smulders; Saskia Lassche Journal: Clin Genet Date: 2021-08-01 Impact factor: 4.296