Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis

Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skel etal dysplasia characterized by short limbs, short ribs, postaxial polydact yly and dysplastic nails and teeth(1,2). Congenital cardiac defects, most c ommonly a defect of primary atrial septation producing a common atrium, occ ur in 60% of affected individuals. The disease was mapped to chromosome 4p1 6 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil(3). Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region(4). We have identifie d a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in i ndividuals with EvC. We identified a splice-donor change in an Amish pedigr ee and six truncating mutations and a single amino acid deletion in seven p edigrees. The heterozygous carriers of these mutations did not manifest fea tures of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic: conditions.