Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

Autor:	Altunoglu U; Medical Genetics Department, School of Medicine (KUSoM), Koç University, Istanbul, Turkey ualtunoglu@ku.edu.tr.; Medical Genetics Department, Istanbul Faculty of Medicine, Istanbul University, Fatih, Turkey., Palencia-Campos A; Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain.; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain., Güneş N; Cerrahpasa Medical Faculty, Department of Pediatric Genetics, Istanbul Universitesi-Cerrahpasa, Istanbul, Turkey., Turgut GT; Medical Genetics Department, Istanbul Faculty of Medicine, Istanbul University, Fatih, Turkey., Nevado J; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Instituto de Genética Médica y Molecular (INGEMM), ITHACA-ERN, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain., Lapunzina P; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Instituto de Genética Médica y Molecular (INGEMM), ITHACA-ERN, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain., Valencia M; Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain., Iturrate A; Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain.; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain., Otaify G; Department of Clinical Genetics, Institute of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt., Elhossini R; Department of Clinical Genetics, Institute of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt., Ashour A; Department of Clinical Genetics, Institute of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt., K Amin A; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt., Elnahas RF; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt., Fernandez-Nuñez E; Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain., Flores CL; Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain.; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain., Arias P; Instituto de Genética Médica y Molecular (INGEMM), ITHACA-ERN, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain., Tenorio J; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Instituto de Genética Médica y Molecular (INGEMM), ITHACA-ERN, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain., Chamorro Fernández CI; Sección de Cardiología, Hospital Virgen de los Lirios de Alcoy, Alicante, Spain., Güven Y; Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul, Turkey., Özsu E; Department of Pediatric Endocrinology and Diabetes, School of Medicine, Ankara University, Ankara, Turkey., Eklioğlu BS; Division of Pediatric Endocrinology, Department of Pediatrics, Necmettin Erbakan University, Konya, Turkey., Ibarra-Ramirez M; Departamento de Genética, Facultad de Medicina, Universidad Autónoma de Nuevo León, Nuevo Leon, Mexico., Diness BR; Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health, University of Copenhagen, Kobenhavn, Denmark., Burnyte B; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania., Ajmi H; Service de Pédiatrie, Centre Hôspitalier Universitaire (CHU) Sahloul, Sousse, Tunisia., Yüksel Z; Human Genetics Department, Bioscientia Healthcare GmbH, Ingelheim, Germany., Yıldırım R; Department of Pediatric Endocrinology, Ministry of Health Diyarbakir Children's Hospital, Diyarbakir, Turkey., Ünal E; Department of Pediatric Endocrinology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey., Abdalla E; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt., Aglan M; Department of Clinical Genetics, Institute of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt., Kayserili H; Medical Genetics Department, School of Medicine (KUSoM), Koç University, Istanbul, Turkey., Tuysuz B; Cerrahpasa Medical Faculty, Department of Pediatric Genetics, Istanbul Universitesi-Cerrahpasa, Istanbul, Turkey., Ruiz-Pérez V; Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain.; CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Instituto de Genética Médica y Molecular (INGEMM), ITHACA-ERN, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2024 Jun 20; Vol. 61 (7), pp. 633-644. Date of Electronic Publication: 2024 Jun 20.
DOI:	10.1136/jmg-2023-109546
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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