Victor L. Ruiz-Perez [1,10], Susan E. Ide [2, 5, 10], Tim M. Strom [3, 10], Bettina Lorenz , David Wilson , Kathryn Woods , Lynn King , Clair Francomano , Peter Freisinger , Stephanie Spranger , Bruno Marino , Bruno Dallapiccola , Michael Wright , Thomas Meitinger , Mihael H. Polymeropoulos , and Judith Goodship , "Mutations in a New Gene in Ellis-van Creveld Syndrome and Weyers Acrodental Dysostosis," Vol. 24, No. 3, pp. 283-286, Nature Genetics (March 2000).
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 4 (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.
1. Human Genetics Unit, School of Biochemistry and Genetics, Newcastle University, Newcastle upon Tyne; UK.
2. Novartis Pharmaceuticals Corporation, Pharmacogenetics Division, Gaithersburg, Maryland; USA.
3. Abteilung Medizinische Genetik, Klinikum Innenstadt, Ludwig-Maximilians-UniversitĄt, MĀnchen; Germany.
4. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; USA.
5. George Washington University, Graduate Genetics Program GWIBS, Washington, DC; USA.
6. Kinderklinik der Technischen UniveristĄt, MĀnchen; Germany.
7. Centre for Human Genetics, University of Bremen, Bremen; Germany.
8. Ospedale Pediatrico Bambino Gesu, Rome; Italy.
9. La Sapienza University, CSS-Mendel Institute, Rome; Italy.
These authors contributed equally to this work.
Correspondence should be addressed to Judith Goodship.
Amish Dwarfism Gene
Joseph B. Verrengia,
AP Science Writer
5:01 PM EST; 03/01/00; (AP) -- Scientists have located the gene associated with a form of dwarfism and related birth defects most commonly seen in the Amish. The scientists found that mutations in the gene trigger Ellis-van Creveld Syndrome which causes skeletal deformities during an embryo's early stages. Researchers said that locating the gene and understanding how it mutates will help explain the basis for human growth and movement. The study by researchers in the United States and Europe appears in the March issue of the journal Nature Genetics.
The discovery highlights a growing collaboration between scientists and the Old Order Amish of Lancaster County, PA. Researchers traced 50 cases of Ellis-Van Creveld in Lancaster County to a couple who emigrated to eastern Pennsylvania in 1744. Ellis-Van Creveld was first described by doctors in the year 1940. It is most commonly seen in Old Order Amish, whose religious beliefs require them to live apart from modern society, and other closed cultures that intermarry. Babies born with the disorder are characterized by dwarfism, shortened limbs, polydactyly (extra fingers and toes), and mouth deformities. At least half develop ASD (holes between the upper chambers of their hearts). Many of the problems can be surgically corrected, but there is no cure for the condition.
The gene's identification provides the basis for premarital and prenatal testing. But Amish couples would probably not submit to such tests because of their strict religious beliefs and marriage customs. "They simply accept people with the syndrome as part of the culture," said Dr. Holmes Morton, who runs the Clinic for Special Children for the Amish in Strasburg, Pennsylvania.