Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1996 Feb;58(2):384–392.

Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.

J E Reynolds 1, M L Marazita 1, J M Meyer 1, C A Stevens 1, L J Eaves 1, K S Arnos 1, L M Ploughman 1, C MacLean 1, W E Nance 1, S R Diehl 1
PMCID: PMC1914540  PMID: 8571965

Abstract

We used segregation analysis to investigate the genetic basis of variation in dystopia canthorum, one of the key diagnostic features of Waardenburg syndrome type 1 (WS1). We sought to determine whether the W-index, a quantitative measure of this craniofacial feature, is influenced primarily either by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. We studied both WS1-affected individuals and their WS1-unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations are consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggest that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influence variation in dystopia canthorum. Our approach should be applicable for assessing the genetic architecture of variation associated with other genetic diseases.

Full text

PDF
384

Images in this article

385Figure 1
on p.385

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arias S., Mota M. Apparent non-penetrance for dystopia in Waardenburg syndrome type I, with some hints on the diagnosis of dystopia canthorum. J Genet Hum. 1978 Jun;26(2):103–131. [PubMed] [Google Scholar]
  2. Demenais F. M., Bonney G. E. Equivalence of the mixed and regressive models for genetic analysis. I. Continuous traits. Genet Epidemiol. 1989;6(5):597–617. doi: 10.1002/gepi.1370060505. [DOI] [PubMed] [Google Scholar]
  3. Easton D. F., Ponder M. A., Huson S. M., Ponder B. A. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993 Aug;53(2):305–313. [PMC free article] [PubMed] [Google Scholar]
  4. Epstein D. J., Vekemans M., Gros P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell. 1991 Nov 15;67(4):767–774. doi: 10.1016/0092-8674(91)90071-6. [DOI] [PubMed] [Google Scholar]
  5. Farrer L. A., Arnos K. S., Asher J. H., Jr, Baldwin C. T., Diehl S. R., Friedman T. B., Greenberg J., Grundfast K. M., Hoth C., Lalwani A. K. Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes. Am J Hum Genet. 1994 Oct;55(4):728–737. [PMC free article] [PubMed] [Google Scholar]
  6. Farrer L. A., Grundfast K. M., Amos J., Arnos K. S., Asher J. H., Jr, Beighton P., Diehl S. R., Fex J., Foy C., Friedman T. B. Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium. Am J Hum Genet. 1992 May;50(5):902–913. [PMC free article] [PubMed] [Google Scholar]
  7. Foy C., Newton V., Wellesley D., Harris R., Read A. P. Assignment of the locus for Waardenburg syndrome type I to human chromosome 2q37 and possible homology to the Splotch mouse. Am J Hum Genet. 1990 Jun;46(6):1017–1023. [PMC free article] [PubMed] [Google Scholar]
  8. Hageman M. J., Delleman J. W. Heterogeneity in Waardenburg syndrome. Am J Hum Genet. 1977 Sep;29(5):468–485. [PMC free article] [PubMed] [Google Scholar]
  9. Rave-Harel N., Madgar I., Goshen R., Nissim-Rafinia M., Ziadni A., Rahat A., Chiba O., Kalman Y. M., Brautbar C., Levinson D. CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens. Am J Hum Genet. 1995 Jun;56(6):1359–1366. [PMC free article] [PubMed] [Google Scholar]
  10. Reynolds J. E., Arnos K. S., Landa B., Stevens C. A., Salbert B. A., Wright L., Duke B., Hunt W., Marazita M. L., Ploughman L. Analysis of locus heterogeneity in Waardenburg syndrome types 1 and 2 using highly informative microsatellite markers. Hum Hered. 1995 Sep-Oct;45(5):243–252. doi: 10.1159/000154307. [DOI] [PubMed] [Google Scholar]
  11. Reynolds J. E., Meyer J. M., Landa B., Stevens C. A., Arnos K. S., Israel J., Marazita M. L., Bodurtha J., Nance W. E., Diehl S. R. Analysis of variability of clinical manifestations in Waardenburg syndrome. Am J Med Genet. 1995 Jul 17;57(4):540–547. doi: 10.1002/ajmg.1320570405. [DOI] [PubMed] [Google Scholar]
  12. Stevens C., Arnos K., Bodurtha J., Wright L., Rawlings B., Marazita M., Nance W., Diehl S. Ascertainment of families with hereditary deafness for linkage studies. Waardenburg and Usher syndromes. Ann N Y Acad Sci. 1991;630:293–294. doi: 10.1111/j.1749-6632.1991.tb19610.x. [DOI] [PubMed] [Google Scholar]
  13. WAARDENBURG P. J. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet. 1951 Sep;3(3):195–253. [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES