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

Abstract

BackgroundEllis-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 inEVCorEVC2. 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.MethodsWe 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 resultsWe identified pathogenic variants inEVC/EVC2in 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 inWDR35and a de novo heterozygous frameshift variant inGLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novelEVC2C-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.ConclusionsThis 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 theEVC/EVC2mutational landscape and addGLI3to the list of genes associated with EvC-like phenotypes.