Marie-Cécile Gaillard1, Stéphane Roche1, Camille Dion1, Armand Tasmadjian1, Gwenaëlle Bouget1, Emmanuelle Salort-Campana1, Catherine Vovan1, Charlene Chaix1, Natacha Broucqsault1, Julia Morere1, Francesca Puppo1, Marc Bartoli1, Nicolas Levy1, Rafaëlle Bernard1, Shahram Attarian1, Karine Nguyen1, Frédérique Magdinier2. 1. From Aix Marseille Universite (M.-C.G., S.R., C.D., A.T., G.B., E.S.-C., N.B., J.M., F.P., M.B., N.L., R.B., S.A., K.N., F.M.), INSERM GMGF UMR S_910, Marseille; and APHM, Centre de Référence des Maladies Neuromusculaires et de la SLA (E.S.-C., S.A.), and APHM, Laboratoire de Génétique Médicale (C.V., C.C., N.L., R.B., K.N.), Hôpital de la Timone, Marseille, France. 2. From Aix Marseille Universite (M.-C.G., S.R., C.D., A.T., G.B., E.S.-C., N.B., J.M., F.P., M.B., N.L., R.B., S.A., K.N., F.M.), INSERM GMGF UMR S_910, Marseille; and APHM, Centre de Référence des Maladies Neuromusculaires et de la SLA (E.S.-C., S.A.), and APHM, Laboratoire de Génétique Médicale (C.V., C.C., N.L., R.B., K.N.), Hôpital de la Timone, Marseille, France. frederique.magdinier@univ-amu.fr.
Abstract
OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and could not thus far be correlated with disease presence or severity. METHODS: To investigate the link between clinical signs of FSHD and DNA methylation, we explored 95 cases (37 FSHD1, 29 asymptomatic individuals carrying a shortened D4Z4 array, 9 patients with FSHD2, and 20 controls) by implementing 2 approaches: methylated DNA immunoprecipitation and sodium bisulfite sequencing. RESULTS: Both methods revealed statistically significant differences between asymptomatic carriers or controls and individuals with clinical FSHD, especially in the proximal region of the repeat. Absence of clinical expression in asymptomatic carriers is associated with a level of methylation similar to controls. CONCLUSIONS: We provide a proof of concept that the targeted approaches that we describe could be applied systematically to patient samples in routine diagnosis and suggest that local hypomethylation within D4Z4 might serve as a modifier for clinical expression of FSHD phenotype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD.
OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and could not thus far be correlated with disease presence or severity. METHODS: To investigate the link between clinical signs of FSHD and DNA methylation, we explored 95 cases (37 FSHD1, 29 asymptomatic individuals carrying a shortened D4Z4 array, 9 patients with FSHD2, and 20 controls) by implementing 2 approaches: methylated DNA immunoprecipitation and sodium bisulfite sequencing. RESULTS: Both methods revealed statistically significant differences between asymptomatic carriers or controls and individuals with clinical FSHD, especially in the proximal region of the repeat. Absence of clinical expression in asymptomatic carriers is associated with a level of methylation similar to controls. CONCLUSIONS: We provide a proof of concept that the targeted approaches that we describe could be applied systematically to patient samples in routine diagnosis and suggest that local hypomethylation within D4Z4 might serve as a modifier for clinical expression of FSHD phenotype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD.
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