Human Genetics

, Volume 102, Issue 5, pp 499–506

Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations

  • 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
Original investigation

DOI: 10.1007/s004390050732

Cite this article as:
DeStefano, A., Cupples, L., Arnos, K. et al. Hum Genet (1998) 102: 499. doi:10.1007/s004390050732

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.

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Anita L. DeStefano
    • 1
  • L. Adrienne Cupples
    • 2
  • Kathleen S. Arnos
    • 4
  • J. H. Jr. Asher
    • 5
  • Clinton T. Baldwin
    • 3
  • Susan Blanton
    • 6
  • Melisa L. Carey
    • 5
  • Elias O. da Silva
    • 7
  • T. B. Friedman
    • 5
  • Jacquie Greenberg
    • 8
  • Anil K. Lalwani
    • 9
  • Aubrey Milunsky
    • 3
  • Walter E. Nance
    • 6
  • Arti Pandya
    • 6
  • Rajkumar S. Ramesar
    • 8
  • Andrew P. Read
    • 10
  • May Tassabejhi
    • 10
  • Edward R. Wilcox
    • 11
  • L. A. Farrer
    • 1
  1. 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.eduUS
  2. 2.Department Epidemiology and Biostatistics, Boston University School of Medicine, Boston, MA 02118, USAUS
  3. 3.Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118, USAUS
  4. 4.Gallaudet University, Washington, DC 20002 , USAUS
  5. 5.Department of Zoology and Genetics Graduate Program, Michigan State University, East Lansing, MI 48824, USAUS
  6. 6.Department of Human Genetics, Virginia Commonwealth University, Richmond, VA 23298, USAUS
  7. 7.Department of Genetics, Federal University of Pernambuco, Recife, BrazilBR
  8. 8.Department of Human Genetics, University of Cape Town, Cape Town, South AfricaZA
  9. 9.Department of Otolaryngology, University of California, San Francisco, CA 94117, USAUS
  10. 10.University of Manchester, Manchester, United KingdomGB
  11. 11.National Institute on Deafness and other Communication Disorders, NIH, Bethesda, MD 20892, USAUS