Nonsyndromic orofacial clefts (OFCs) of the lip with or without cleft palate (CL/P) or of the palate only (CPO) comprise a significant proportion of human birth defects (about 1/700 live births worldwide). OFCs require surgical, nutritional, dental, speech, medical and behavioral interventions, and thus impose substantial public health, economic, and personal burdens. During the previous funding periods of this project, we achieved all our delineated goals and unequivocally established the rich phenotyping paradigm that our research group has developed over the last decade. Our subclinical phenotyping approach has the potential to help define mechanisms that lead to OFCs and provide improved prediction of individual risks for these defects. Subclinical expressions of OFC (e.g., subtle speech abnormalities) that are distributed within affected families can reveal clues about etiology. Numerous genes/loci have now been identified for overt OFC, based largely on recent genome-wide association studies resulting from the present funding period. The current grant proposal is a renewal of grant #R01-DE016148, now in its second funding period. The overarching goal of this renewal remains consistent, i.e. to incorporate subclinical phenotypic features into etiologic studies of OFCs in an effort to both improve our understanding of genetic and other risk factors underlying these birth defects and to facilitate the translation of this improved understanding to clinical applications.
The specific aims for this renewal follow directly from the discoveries of the previous funding periods, i.e. to: (1) further characterize patterns of subclinical OFC phenotypes in cleft families;(2) uncover the genetic basis of overt forms of OFC;(3) discover the genetic basis of subclinical OFC-related phenotypes. Our previous findings also serve to underscore the fact that different populations/ethnicities, as well as different forms of clefting, are likely characterized by distinct etiological profiles. Our present proposal aims to address this issue directly by recruiting understudied, yet etiologically informative, populations (i.e., Sub-Saharan Africans) and less well understood forms of clefting (i.e. CPO). We will continue our successful genetic studies in OFC families, incorporating both well-established and novel subclinical phenotypes into formal gene identification approaches. Our proposal will potentially translate the findings from human genetic studies into strategies that can be eventually assessed through robust clinical studies, with the ultimate goal of improving the standard of care of individuals with OFCs.

Public Health Relevance

The goal of this renewal is to continue to investigate sub-clinical phenotypic features in nonsyndromic orofacial cleft families, with an emphasis on how such features clarify the genetics of orofacial birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE016148-09A1
Application #
8691130
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Harris, Emily L
Project Start
2004-07-01
Project End
2019-08-31
Budget Start
2014-09-11
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$1,964,100
Indirect Cost
$517,329
Name
University of Pittsburgh
Department
Dentistry
Type
Schools of Dentistry
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Leslie, Elizabeth J; Carlson, Jenna C; Cooper, Margaret E et al. (2016) Exploring Subclinical Phenotypic Features in Twin Pairs Discordant for Cleft Lip and Palate. Cleft Palate Craniofac J :
Leslie, E J; Koboldt, D C; Kang, C J et al. (2016) IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families. Clin Genet 90:28-34
Leslie, Elizabeth J; Liu, Huan; Carlson, Jenna C et al. (2016) A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. Am J Hum Genet 98:744-54
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Wise, Alison S; Shi, Min; Weinberg, Clarice R (2016) Family-Based Multi-SNP X Chromosome Analysis Using Parent Information. Front Genet 7:20
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2016) A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13. Hum Mol Genet 25:2862-2872
Gowans, L J J; Adeyemo, W L; Eshete, M et al. (2016) Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations. J Dent Res 95:1245-56
Weinberg, Seth M; Raffensperger, Zachary D; Kesterke, Matthew J et al. (2016) The 3D Facial Norms Database: Part 1. A Web-Based Craniofacial Anthropometric and Image Repository for the Clinical and Research Community. Cleft Palate Craniofac J 53:e185-e197

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