As a pediatric geneticist, the P.I. has a keen interest in understanding the molecular pathology of inherited disorders, especially in children. The long term goal is to establish a career in academic medicine, which would allow the PI to study the importance of modifier genes for phenotypic variation in clinically relevant genetic disorders. Current Departmental projects are highly relevant to this proposal and will provide the necessary building blocks for the PI's career development. Hearing loss affects at least 5 percent of the population with the incidence of profound deafness at birth or during early childhood being estimated as about 0.8 per 1000. It is etiologically heterogenous, with genetic factors accounting for half of all cases of profound deafness, 10-20 percent of which are due to a specific hereditary syndrome. Waardenburg syndrome (WS) is a symptom complex that includes deafness, dystopia canthorum, white forelock and heterochromia. We participated in mapping the gene to 2q35 region, the discovery of genetic heterogeneity in WS, and in the demonstration of mutational heterogeneity at the PAX3 locus. The extensive phenotypic variation observed within WS1 families combined with the striking concordance for phenotype in MZ twins strongly suggests that modifier gene(s) contribute to this variability. The present proposes to identify and characterize the gene(s) causing deafness in individuals who have inherited a gene for WS type 1. We have identified 22 WS1 families with a minimum of 2 or more WS1 siblings who are both affected with deafness. This is ideal for mapping modifier gene(s) by an """"""""affecteds"""""""" only approach. A two tiered mapping strategy involving a candidate gene search followed by a genome wide scan is proposed. Nonparametric methods of analysis will be used in addition to the traditional parametric approach to extract maximum information from families being studies. We will also further characterize the spectrum of PAX3 mutations in 30 available families with WS1 and study their potential interaction with the modifier gene(s). The successful identification of modifier genes which cause deafness in WS could lead to improved predictive testing.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HD001172-01A1
Application #
2463087
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
1998-08-01
Project End
2003-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Pandya, Arti; Arnos, Kathleen S; Xia, Xia J et al. (2003) Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. Genet Med 5:295-303
Stern, S J; Arnos, K S; Murrelle, L et al. (2002) Attitudes of deaf and hard of hearing subjects towards genetic testing and prenatal diagnosis of hearing loss. J Med Genet 39:449-53
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Tekin, M; Akar, N; Cin, S et al. (2001) Connexin 26 (GJB2) mutations in the Turkish population: implications for the origin and high frequency of the 35delG mutation in Caucasians. Hum Genet 108:385-9
Pandya, A; Xia, X J; Erdenetungalag, R et al. (1999) Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. Am J Hum Genet 65:1803-6