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

An Erratum to this article was published on 01 May 2000

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 teeth1,2. 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 Brazil3. 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 region4. 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.

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Figure 1: Physical map of the region and genomic organization of EVC.
Figure 2: Haplotype analysis in Amish family 3 and Brazilian family 12.
Figure 3: Comparison of human and mouse protein sequence.
Figure 4: DNA sequence showing homozygous mutations in three patients.
Figure 5: Deletion analysis of family EVC015.

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Acknowledgements

We thank A. Verloes, A. Nerlich and I. Young for sending samples from patients, and J. Burn and T. Strachan for encouragement. This work was supported by the British Heart Foundation, Newcastle Hospital Special Trustees, the Knott Trust, the Borwick Trust and the Deutsche Forschungsgemeinschaft.

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Correspondence to Judith Goodship.

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Ruiz-Perez, V., Ide, S., Strom, T. et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24, 283–286 (2000). https://doi.org/10.1038/73508

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