RT Journal Article
SR Electronic
T1 SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2019-106168
DO 10.1136/jmedgenet-2019-106168
A1 Richard J L F Lemmers
A1 Nienke van der Stoep
A1 Patrick J van der Vliet
A1 Steven A Moore
A1 David San Leon Granado
A1 Katherine Johnson
A1 Ana Topf
A1 Volker Straub
A1 Teresinha Evangelista
A1 Tahseen Mozaffar
A1 Virginia Kimonis
A1 Natalie D Shaw
A1 Rita Selvatici
A1 Alessandra Ferlini
A1 Nicol Voermans
A1 Baziel van Engelen
A1 Sabrina Sacconi
A1 Rabi Tawil
A1 Meindert Lamers
A1 Silvère M van der Maarel
YR 2019
UL http://jmg.bmj.com/content/early/2019/09/10/jmedgenet-2019-106168.abstract
AB Background Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype–phenotype relationships.Methods Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1.Results DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1.Conclusions The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.