ABSTRACT
Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. 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. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features 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.
Subject(s)
Chromosomes, Human, Pair 4/genetics , Dysostoses/genetics , Ellis-Van Creveld Syndrome/genetics , Ethnicity/genetics , Genes , Membrane Proteins/genetics , Tooth Abnormalities/genetics , Alternative Splicing , Amino Acid Sequence , Amino Acid Substitution , Base Sequence , Brazil/epidemiology , Chromosome Mapping , Dwarfism/genetics , Ellis-Van Creveld Syndrome/ethnology , Expressed Sequence Tags , Female , Fingers/abnormalities , Genes, Dominant , Heart Defects, Congenital/genetics , Heterozygote , Humans , Incisor/abnormalities , Leucine Zippers/genetics , Male , Membrane Proteins/physiology , Microsatellite Repeats , Molecular Sequence Data , Pedigree , Pennsylvania/epidemiology , Phenotype , Point Mutation , Polymorphism, Single-Stranded Conformational , Proteins , Recombination, Genetic , Reverse Transcriptase Polymerase Chain Reaction , SyndromeABSTRACT
Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.