Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.
Umut Altunoglu, Adrian Palencia-Campos, Nilay Güneş, Gozde Tutku Turgut, Julian Nevado, Pablo Lapunzina, Maria Valencia, Asier Iturrate, Ghada Otaify, Rasha Elhossini, Adel Ashour, Asmaa K Amin, Rania F Elnahas, Elisa Fernandez-Nuñez, Carmen-Lisset Flores, Pedro Arias, Jair Tenorio, Carlos Israel Chamorro Fernández, Yeliz Güven, Elif Özsu, Beray Selver Eklioğlu, Marisol Ibarra-Ramirez, Birgitte Rode Diness, Birute Burnyte, Houda Ajmi, Zafer Yüksel, Ruken Yıldırım, Edip Ünal, Ebtesam Abdalla, Mona Aglan, Hulya Kayserili, Beyhan Tuysuz, Victor Ruiz-Pérez
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引用次数: 0
Abstract
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.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.