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Diagnostics
Original research
Ellis-Van Creveld Syndrome: Clinical and Molecular Analysis of 50 Individuals
  1. Marion Aubert-Mucca1,
  2. Céline Huber2,
  3. Genevieve Baujat1,2,
  4. Caroline Michot1,2,
  5. Mohammed Zarhrate3,
  6. Marc Bras4,
  7. Lucile Boutaud2,5,
  8. Valérie Malan2,5,
  9. Tania Attie-Bitach2,5,
  10. Clinical Contributors,
  11. Valerie Cormier-Daire1,2
    1. 1 Centre de Référence des Maladies Osseuses Constitutionnelles, Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, Paris, France
    2. 2 Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
    3. 3 Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Imagine Institute, Paris, France
    4. 4 Bioinformatics Platform, Imagine Institute, Paris, France
    5. 5 Service de Médecine Génomique des Maladies Rares, Hopital Universitaire Necker-Enfants Malades, Paris, France
    1. Correspondence to Professor Valerie Cormier-Daire, Centre de Référence des Maladies Osseuses Constitutionnelles, Service de médecine génomique des maladies rares, Hôpital universitaire Necker-Enfants malades, Paris 75015, France; valerie.cormier-daire{at}inserm.fr

    Abstract

    Background Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib–polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The EVC and EVC2 genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely, WDR35, GLI1, DYNC2LI1, PRKACA, PRKACB and SMO. They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways.

    Methods The aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC.

    Results Our detection rate in the cohort of 45 families was of 91.11%, with variants identified in EVC/EVC2 (77.8%), DYNC2H1 (6.7%), DYNC2LI1 (2.2%), SMO (2.2%) or PRKACB (2.2%). No distinctive feature was remarkable of a specific genotype–phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in EVC/EVC2 of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences.

    Conclusion We confirmed that EVC and EVC2 are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).

    • Bone Diseases, Endocrine
    • Diagnosis
    • Human Genetics

    Data availability statement

    Data supporting figures 1–4, tables 1–2 and online supplemental tables 1–2 are not publicly available in order to protect patient privacy.

    https://doi.org/10.1136/jmg-2022-108435

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      Data availability statement

      Data supporting figures 1–4, tables 1–2 and online supplemental tables 1–2 are not publicly available in order to protect patient privacy.

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      Footnotes

      • Twitter @M_AubertMucca

      • Collaborators Clinical Contributors: Yves Alembik, Marie-Pierre Alex-Cordier, Jacqueline Aziza, Yline Capri, Laurence Caeymaen, Dominique Carles, Françoise Devillard, Koenraad Devriendt, Anne Dieux, Charlotte Dubucs, Salima El Chehadeh, Laurence Faivre, Christine Francannet, Dominique Gaillard, Marion Gérard, Emmanuelle Ginglinger, Marie Gonzales, Bertrand Isidor, Florence Jobic, Sophie Julia, Valerie Layet, Laetitia Lambert, Sylvie Manouvrier, Dominique Martin-Coignard, Michèle Mathieu, Andre Megarbané, Judith Melki, Geert Mortier, Clotilde Ormieres, Fanny Pelluard, Audrey Putoux, Chloé Quélin, Sabine Sigaudy, Luigina Spaccini, Alain Verloes, Khaloua Zaafrane.

      • Contributors MAM: data collection, data analysis, manuscript writing, manuscript editing; CH/GB/CM/VM/TAB/LB: data collection, manuscript editing; MZ and MB: software; VCD: guarantor, study conception, data collection, data analysis, manuscript writing, manuscript editing; clinical contributors: data collection. All authors read and approved the final manuscript.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.