Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations |
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| Authors: | Anita L DeStefano L Adrienne Cupples Kathleen S Arnos J H Jr Asher Clinton T Baldwin Susan Blanton Melisa L Carey Elias O da Silva T B Friedman Jacquie Greenberg Anil K Lalwani Aubrey Milunsky Walter E Nance Arti Pandya Rajkumar S Ramesar Andrew P Read May Tassabejhi Edward R Wilcox L A Farrer |
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| Institution: | (1) Department of Neurology, Boston University School of Medicine, 80 East Concord Street, Boston, MA 02118, USA Tel.: +1-617-638-5393; Fax: +1-617-638-4275; e-mail: farrer@neugen.bu.edu, US;(2) Department Epidemiology and Biostatistics, Boston University School of Medicine, Boston, MA 02118, USA, US;(3) Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118, USA, US;(4) Gallaudet University, Washington, DC 20002 , USA, US;(5) Department of Zoology and Genetics Graduate Program, Michigan State University, East Lansing, MI 48824, USA, US;(6) Department of Human Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA, US;(7) Department of Genetics, Federal University of Pernambuco, Recife, Brazil, BR;(8) Department of Human Genetics, University of Cape Town, Cape Town, South Africa, ZA;(9) Department of Otolaryngology, University of California, San Francisco, CA 94117, USA, US;(10) University of Manchester, Manchester, United Kingdom, GB;(11) National Institute on Deafness and other Communication Disorders, NIH, Bethesda, MD 20892, USA, US |
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| Abstract: | Waardenburg syndrome (WS) type 1 is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary
abnormalities of the eye, hair, and skin, and dystopia canthorum. The phenotype is variable and affected individuals may exhibit
only one or a combination of several of the associated features. To assess the relationship between phenotype and gene defect,
clinical and genotype data on 48 families (271 WS individuals) collected by members of the Waardenburg Consortium were pooled.
Forty-two unique mutations in the PAX3 gene, previously identified in these families, were grouped in five mutation categories: amino acid (AA) substitution in
the paired domain, AA substitution in the homeodomain, deletion of the Ser-Thr-Pro-rich region, deletion of the homeodomain
and the Ser-Thr-Pro-rich region, and deletion of the entire gene. These mutation classes are based on the structure of the
PAX3 gene and were chosen to group mutations predicted to have similar defects in the gene product. Association between mutation
class and the presence of hearing loss, eye pigment abnormality, skin hypopigmentation, or white forelock was evaluated using
generalized estimating equations, which allowed for incorporation of a correlation structure that accounts for potential similarity
among members of the same family. Odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation
were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the Pro-Ser-Thr-rich region
compared to individuals with an AA substitution in the homeodomain. Odds ratios that differ significantly from 1.0 for these
traits may indicate that the gene products resulting from different classes of mutations act differently in the expression
of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for AA substitution in the
paired domain compared with AA substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.
Received: 27 July 1997 / Accepted: 9 December 1997 |
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