1 research outputs found
Common atrium/atrioventricular canal defect and postaxial polydactyly: A mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene
Clinical expression of Ellisâvan Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical spliceâsite inâframe change (c.1316â7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patientâderived fibroblasts and Evcâ/â mouse embryonic fibroblasts showed that p.Arg622Ter is a lossâofâfunction mutation, whereas p.Arg663Pro and the spliceâsite change c.1316â7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as âcommon atrium/AVCD with postaxial polydactylyâ is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotypeâphenotype correlations in this syndrome.This study was supported by funding from the Italian Ministry of Health (RCâ2019) to Alessandro De Luca, Fondazione Bambino GesĂč (Vite Coraggiose) to Marco Tartaglia, and the Spanish Ministry of Science, Innovation and Universities to Victor L. RuizâPerez (SAF2016â75434âR (AEI/FEDER, UE) and PID2019â105620RBâI00/AEI/10.13039/501100011033)