Journal article
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
Journal of medical genetics, Vol.56(10), pp.693-700
10/2019
DOI: 10.1136/jmedgenet-2019-106168
PMCID: PMC6800092
PMID: 31243061
Abstract
BackgroundVariants 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.MethodsExamination 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.ConclusionsThe localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.
Details
- Title: Subtitle
- 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
- Creators
- Richard J L F Lemmers - Leiden University Medical CenterNienke van der Stoep - Leiden University Medical CenterPatrick J van der Vliet - Human Genetics, Leids Universitair Medisch Centrum, Leiden, The NetherlandsSteven A Moore - University of IowaDavid San Leon Granado - Human Genetics, Leids Universitair Medisch Centrum, Leiden, The NetherlandsKatherine Johnson - Newcastle UniversityAna Topf - Newcastle UniversityVolker Straub - Newcastle UniversityTeresinha Evangelista - Unité de Morphologie NeuromusculaireTahseen Mozaffar - University of California, IrvineVirginia Kimonis - University of California, IrvineNatalie D Shaw - National Institutes of HealthRita Selvatici - University of FerraraAlessandra Ferlini - University of FerraraNicol Voermans - Department of NeurologyBaziel van Engelen - Department of Neurology, Radboudumc, Nijmegen, Gelderland, The NetherlandsSabrina Sacconi - Centre de Référence Maladies Neuromusculaires, Hôpital ArchetRabi Tawil - University of RochesterMeindert Lamers - Department of Cell and Chemical BiologySilvère M van der Maarel - Leiden University Medical Center
- Resource Type
- Journal article
- Publication Details
- Journal of medical genetics, Vol.56(10), pp.693-700
- DOI
- 10.1136/jmedgenet-2019-106168
- PMID
- 31243061
- PMCID
- PMC6800092
- NLM abbreviation
- J Med Genet
- ISSN
- 0022-2593
- eISSN
- 1468-6244
- Grant note
- name: Iowa Wellstone Muscular Dystrophy Cooperative Research Center, U54, award: NS053672; DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases, award: R01AR045203; DOI: 10.13039/501100004243, name: Prinses Beatrix Spierfonds, award: W.OB17-01, W.OP14-01, W.OR12-20; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke, award: P01NS069539
- Language
- English
- Date published
- 10/2019
- Academic Unit
- Pathology
- Record Identifier
- 9984186400102771
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