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 , SyndromeSubject(s)
Ellis-Van Creveld Syndrome/genetics , Ethnicity/genetics , Founder Effect , Proteins/genetics , Cartilage Diseases/ethnology , Cartilage Diseases/genetics , Community-Institutional Relations , Consanguinity , Dwarfism/classification , Dwarfism/ethnology , Dwarfism/genetics , Ellis-Van Creveld Syndrome/ethnology , Ellis-Van Creveld Syndrome/history , Ethnicity/history , Female , Finland/ethnology , Gene Frequency , Genes, Recessive , Genetics, Population , Germany/ethnology , Hair Diseases/ethnology , Hair Diseases/genetics , History, 18th Century , Humans , Introns/genetics , Leucine Zippers/genetics , Male , Membrane Proteins , Pennsylvania , Switzerland/ethnology , SyndromeABSTRACT
The first reported case of Ellis--van Creveld syndrome in a Gurkha child is described, and the implications of the syndrome in this ethnic group are briefly considered.
Subject(s)
Ellis-Van Creveld Syndrome , Ellis-Van Creveld Syndrome/ethnology , Ellis-Van Creveld Syndrome/pathology , Female , Genetic Counseling , Humans , Infant, Newborn , NepalABSTRACT
Ellis van Creveld syndrome (EVC) is an autosomal recessive disorder which has previously been mapped to human chromosome 4p16.1. This disorder is characterized by disproportionate dwarfism, polydactyly, cleft palate, natal teeth, and congenital heart disease. The MSX1 homeobox gene also maps to the 4p16.1 region. Msx gene transcripts in the mouse embryo are known to be involved in pattern formation of the developing limb bud and craniofacial bones. Thus, on the basis of both map location and known gene function, MSX1 was an excellent candidate as the causative gene for EVC. Nonetheless, direct DNA sequencing of both exons of the MSX1 gene in five affected individuals segregating with the EVC phenotype, as well as those of two obligate carriers, revealed no mutations in the coding region of the gene.
Subject(s)
Christianity , Ellis-Van Creveld Syndrome/genetics , Genes, Homeobox , Homeodomain Proteins/genetics , Transcription Factors , Amino Acid Sequence , Animals , Base Sequence , Chromosomes, Human, Pair 4 , Ellis-Van Creveld Syndrome/ethnology , Exons , Humans , MSX1 Transcription Factor , Mice , Molecular Sequence Data , PennsylvaniaABSTRACT
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.