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SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance

European Journal of Human Genetics volume 33, pages 784–792 (2025) Cite this article

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Abstract

The molecular diagnosis of type 1 facioscapulohumeral muscular dystrophy (FSHD1) relies on the detection of a shortened D4Z4 array at the 4q35 locus. Until recently, the diagnosis of FSHD2 relied solely on the absence of a shortened D4Z4 allele in clinically affected patients. It is now established that most FSHD2 cases carry a heterozygous variant in the SMCHD1 gene. A decrease in D4Z4 DNA methylation is observed in both FSHD1 and FSHD2 patients. To refine the molecular diagnosis of FSHD2, we performed a molecular diagnosis of SMCHD1 in 54 patients with a clinical diagnosis of FSHD. All patients carry a D4Z4 array of more than 10 D4Z4 units, or a cis-duplication of the locus. Forty-eight of them carry a variant in SMCHD1 and six other cases are hemizygous for the 18p32 locus encompassing SMCHD1. Genetic and epigenetic analyses were considered to assess the pathogenicity of new SMCHD1 variants and of variants previously classified as likely pathogenic. In comparison to the healthy population and FSHD1 patients, we defined a threshold of 40% of methylation at the D4Z4 DR1 site as associated with SMCHD1 variants or SMCHD1 hemizygosity. We also showed that the number of D4Z4 on the shortest 4q allele ranges from 11 up to 35 units in these same patients. Using variant interpretation and protein structure prediction tools, we also highlight the difficulty in interpreting the impact of pathogenic variants on SMCHD1 function. Our study further emphasizes the intriguing relationship between D4Z4 methylation, SMCHD1 variants with SMCHD1 protein structure-function in FSHD.

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Fig. 1: Size of the shortest D4Z4 alleles in patients carrying a variant in SMCHD1 and D4Z4 methylation level.
The alternative text for this image may have been generated using AI.
Fig. 2: Prediction of the deleterious impact of missense variant on SMCHD1 function.
The alternative text for this image may have been generated using AI.
Fig. 3: Workflow for the characterization of SMCHD1 variants in FSHD2 diagnosis.
The alternative text for this image may have been generated using AI.

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Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files]. SMCHD1 variants were deposited in the LOVD database https://databases.lovd.nl/shared/genes/SMCHD1.

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Acknowledgements

We are indebted and thank all patients for participating in this study.

Funding

This study was funded by “Association Française contre les Myopathies” (AFM Téléthon; TRIM-RD; MoThARD grants) and Agence Nationale pour la Recherche, ANR-21-CE45-0001-01. The project leading to this publication has received funding from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir program” AMX-19-IET-007. CL and MD are the recipient of a fellowship from the French Ministry of Higher Education and Research.

Author information

Author notes

  1. These authors contributed equally: Laurène Gérard, Mégane Delourme, Charlotte Tardy, Rafaëlle Bernard, Frédérique Magdinier.

Authors and Affiliations

  1. Service de Génétique Médicale, Biogénopôle, Hôpitaux Universitaires de Marseille, Marseille, France

    Laurène Gérard, Charlotte Tardy, Charlene Chaix, Karine Bertaux, Chantal Missirian, Karine Nguyen & Rafaëlle Bernard

  2. Aix-Marseille Univ-INSERM, Marseille Medical Genetics, Marseille, France

    Mégane Delourme, Charlotte Tardy, Benjamin Ganne, Pierre Perrin, Jean Philippe Trani, Nathalie Eudes, Camille Laberthonnière, Chantal Missirian, Emmanuelle Salort Campana, Shahram Attarian, Karine Nguyen, Ali Badache, Rafaëlle Bernard & Frédérique Magdinier

  3. Centre de ressources Biologiques, Biogénopôle, Hôpitaux Universitaires de Marseille, Biogénopôle, 13005, Marseille, France

    Karine Bertaux

  4. APHP, Service de Neuromyologie, Institut de Myologie, GH Pitié-Salpêtrière, Paris, France

    Guillaume Bassez, Anthony Behin, Teresinha Evangelista & Tanya Stojkovic

  5. Neuromuscular Morphology Unit, Neuromuscular Investigation Center, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France

    Guillaume Bassez & Teresinha Evangelista

  6. Centre de référence neuromusculaire, CHU Toulouse Purpan, Toulouse, France

    Pascal Cintas

  7. Electroneuromyography and Neuromuscular Diseases Unit, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France

    Florent Cluse, Antoine Pegat & Juliette Svahn

  8. Département de Neurologie, CHU Gui de Chauliac, Montpellier, France

    Elisa De La Cruz

  9. Centre de références des Maladies neuromusculaires et de la SLA, Hôpitaux Universitaires de Marseille, Hôpital Timone Adulte, Marseille, France

    Emilien Delmont, Ludivine Kouton, Emmanuelle Salort Campana & Shahram Attarian

  10. Service de génétique Médicale CHU Rennes, Rennes, Centre de Compétences Maladies Neuromusculaires de Rennes, Rennes, France

    Mélanie Fradin

  11. INSERM-Université Bourgogne U1231, Equipe GAD Génétique des Anomalies du Développement Dijon, Dijon, France

    Nawale Hadouiri & Christel Thauvin

  12. Pôle Rééducation-Réadaptation, CHU Dijon-Bourgogne, Dijon, France

    Nawale Hadouiri

  13. Neurology Department, Raymond Poincaré University Hospital, Garches, APHP, Paris, France

    Pascal Laforêt & Claire Lefeuvre

  14. Nord-Est-Ile-de-France Neuromuscular Reference Center, Ile-de-Franc, FHU PHENIX, France

    Pascal Laforêt

  15. Centre de Référence des Maladies Neuromusculaires AOC, CHU de Nantes, Filnemus, Euro-NMD, Nantes, France

    Armelle Magot

  16. L’Escale, Service de Médecine Physique et de Réadaptation Pédiatrique, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Groupement Est, Bron, France

    Véronique Manel

  17. Service de Médecine Génomique des Maladies de Système et d’Organe, Fédération de Génétique et de Médecine Génomique, APHP Centre - Université Paris Cité, Hôpital Cochin, 75014, Paris, France

    Juliette Nectoux & Camille Verebi

  18. Centre de Référence des Maladies Neuromusculaires AOC, Service de Neurologie et Maladies Neuromusculaires, FILNEMUS, EURONMD, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France

    Guilhem Sole

  19. Neuromuscular Reference Center, Department of Neurology, CHU d’Angers, d’Angers, France

    Marco Spinazzi

  20. Univ. Lille, Inserm, CHU Lille, U1172 – LilNCog – Lille Neuroscience & Cognition, F-59000, Lille, France

    Celine Tard

  21. Centre de référence des maladies neuromusculaires Nord/Est/Ile- de- France, Lille, France

    Celine Tard

  22. Centre de Génétique, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France

    Christel Thauvin

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  1. Laurène Gérard
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  2. Mégane Delourme
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  40. Frédérique Magdinier
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Contributions

LG and CC performed Molecular Combing for the diagnosis of patients. MD, CT, BG, PP, NE, CL and JPT conducted the DNA methylation experiments and analyzed the data. AB performed the protein prediction analyses and edited the manuscript. RB, KB, CM, CT and KN provided patients’ samples and clinical data, analyzed the data and edited the manuscript. GB, AB, PC, FC, ADLC, ED, TE, MF, NH, LK, PL, CL, AM, VM, JN, AP, GS, MS, TS, JS, CT, CT, CV, ESC, SA provided patients’ samples and clinical expertise. FM designed and supervised the study, obtained funding, analyzed the data, wrote and edited the manuscript.

Corresponding author

Correspondence to Frédérique Magdinier.

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Competing interests

The authors declare no competing interests.

Ethical approval

All individuals have provided written informed consent for the use of DNA sample for medical research and the study was done in accordance with the Declaration of Helsinki. Samples were provided by the Center for biological Resources (Department of Medical Genetics, La Timone Children’s hospital) with the AC 2011-1312 and N°IE-2013-710 accreditation numbers.

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Gérard, L., Delourme, M., Tardy, C. et al. SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance. Eur J Hum Genet 33, 784–792 (2025). https://doi.org/10.1038/s41431-024-01781-x

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