ArticleEuropean journal of human genetics : EJHG2016
Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2.
Article in European journal of human genetics : EJHG, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance.European journal of human genetics : EJHG · 2025Article
- Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.Clinical genetics · 2024Review
- SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.Communications biology · 2023Article
- Influence ofInternational journal of molecular sciences · 2023Review
- Facioscapulohumeral muscular dystrophy: the road to targeted therapies.Nature reviews. Neurology · 2023Review
- IntronicJournal of medical genetics · 2019Article
- 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 · 2019Article
- SMCHD1 terminates the first embryonic genome activation event in mouse two-cell embryos and contributes to a transcriptionally repressive state.American journal of physiology. Cell physiology · 2019Article
- A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1.Neurology · 2018Observational
- Novel key roles for structural maintenance of chromosome flexible domain containing 1 (Smchd1) during preimplantation mouse development.Molecular reproduction and development · 2018Article
- Digenic Inheritance of Shortened Repeat Units of the D4Z4 Region and a Loss-of-Function Variant inFrontiers in neurology · 2018Article
- SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.Nature genetics · 2017Article
- Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report.BMC medical genetics · 2016Article
- Genetic and epigenetic contributors to FSHD.Current opinion in genetics & development · 2015Review
- Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 function-affecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.
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