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Original research
Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis
  1. Umut Altunoglu1,2,
  2. Adrian Palencia-Campos3,4,
  3. Nilay Güneş5,
  4. Gozde Tutku Turgut2,
  5. Julian Nevado4,6,
  6. Pablo Lapunzina4,6,
  7. Maria Valencia3,
  8. Asier Iturrate3,4,
  9. Ghada Otaify7,
  10. Rasha Elhossini7,
  11. Adel Ashour7,
  12. Asmaa K. Amin8,
  13. Rania F Elnahas8,
  14. Elisa Fernandez-Nuñez3,
  15. Carmen-Lisset Flores3,4,
  16. Pedro Arias6,
  17. Jair Tenorio4,6,
  18. Carlos Israel Chamorro Fernández9,
  19. Yeliz Güven10,
  20. Elif Özsu11,
  21. Beray Selver Eklioğlu12,
  22. Marisol Ibarra-Ramirez13,
  23. Birgitte Rode Diness14,15,
  24. Birute Burnyte16,
  25. Houda Ajmi17,
  26. Zafer Yüksel18,
  27. Ruken Yıldırım19,
  28. Edip Ünal20,
  29. Ebtesam Abdalla8,
  30. Mona Aglan7,
  31. Hulya Kayserili1,
  32. Beyhan Tuysuz5,
  33. Victor Ruiz-Pérez3,4,6
  1. 1 Medical Genetics Department, School of Medicine (KUSoM), Koç University, Istanbul, Turkey
  2. 2 Medical Genetics Department, Istanbul Faculty of Medicine, Istanbul University, Fatih, Turkey
  3. 3 Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain
  4. 4 CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
  5. 5 Cerrahpasa Medical Faculty, Department of Pediatric Genetics, Istanbul Universitesi-Cerrahpasa, Istanbul, Turkey
  6. 6 Instituto de Genética Médica y Molecular (INGEMM), ITHACA-ERN, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain
  7. 7 Department of Clinical Genetics, Institute of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt
  8. 8 Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
  9. 9 Sección de Cardiología, Hospital Virgen de los Lirios de Alcoy, Alicante, Spain
  10. 10 Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul, Turkey
  11. 11 Department of Pediatric Endocrinology and Diabetes, School of Medicine, Ankara University, Ankara, Turkey
  12. 12 Division of Pediatric Endocrinology, Department of Pediatrics, Necmettin Erbakan University, Konya, Turkey
  13. 13 Departamento de Genética, Facultad de Medicina, Universidad Autónoma de Nuevo León, Nuevo Leon, Mexico
  14. 14 Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
  15. 15 Department of Clinical Medicine, Faculty of Health, University of Copenhagen, Kobenhavn, Denmark
  16. 16 Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
  17. 17 Service de Pédiatrie, Centre Hôspitalier Universitaire (CHU) Sahloul, Sousse, Tunisia
  18. 18 Human Genetics Department, Bioscientia Healthcare GmbH, Ingelheim, Germany
  19. 19 Department of Pediatric Endocrinology, Ministry of Health Diyarbakir Children's Hospital, Diyarbakir, Turkey
  20. 20 Department of Pediatric Endocrinology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
  1. Correspondence to Dr Umut Altunoglu, Medical Genetics Department, School of Medicine (KUSoM), Koç University, Istanbul, Turkey; ualtunoglu{at}


Background Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.

Methods We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays.

Main results We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated ‘classical EvC findings’ in the literature and highlighted findings previously undescribed or rarely described as part of EvC.

Conclusions This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

  • Congenital, Hereditary, and Neonatal Diseases and Abnormalities
  • Human Genetics
  • Molecular Medicine
  • Pediatrics

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • X @ElisaFernndez1

  • UA and AP-C contributed equally.

  • Contributors UA, HK and VR-P designed the study and coordinated the international collaboration. UA and VR-P drafted the manuscript with the help of GTT and C-LF. UA, NG, GTT, GO, RE, AA, AK, RFE, CICF, YG, EÖ, BSE, MI-R, BRD, BB, HA, ZY, RY, EÜ, EA, MA, HK and BT provided clinical data and collected patient samples. AP-C, JN, PL, MV, AI, EF-N, C-LF, PA, JT and VR-P performed molecular analyses and interpretation of molecular data. UA and GTT analysed phenotypic data. VR-P is responsible for the overall content as guarantor. All authors read and approved the final manuscript.

  • Funding This work was funded by the Spanish Ministry of Economy and Competitiveness (SAF2010-17901, SAF2013-43365-R, SAF2016-75434-R, PID2019-105620RB-I00/AEI/10.13039/501100011033) and FEDER funds through ISCIII grant PI20/01053 and PMP21/00063/Instituto de Salud Carlos III.

  • 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.