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.
- mutation spectrum
- ATPase domain
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Contributors RJLFL and SMvdM contributed to the study design and conception of study. RJLFL, NvdS, PJvdV, SAM, KJ, AT, VS, TE, TM, VK, RS, AF, NV, BvE, SS and RT contributed to the data collection and assembly. RJLFL, NvdS, PJvdV, SAM, DSLG, ML and SMM contributed to the data analysis and interpretation. RJLFL, ML and SMM contributed to the writing of manuscript. RJLFL, NvdS, PJvdV, SAM, NV, ML and SMvdM critical reviewed and revised the manuscript. RJLFL submitted the manuscript.
Funding This study was funded by Iowa Wellstone Muscular Dystrophy Cooperative Research Center, U54 (NS053672) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR045203).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Medical Ethical Committee from the Leiden University Medical Center
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.
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