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.
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.
|Camison, L; Bykowski, M; Lee, W W et al. (2017) Validation of the Vectra H1 portable three-dimensional photogrammetry system for facial imaging. Int J Oral Maxillofac Surg :|
|Liu, Dongjing; Wang, Hong; Schwender, Holger et al. (2017) Gene-gene interaction of single nucleotide polymorphisms in 16p13.3 may contribute to the risk of non-syndromic cleft lip with or without cleft palate in Chinese case-parent trios. Am J Med Genet A 173:1489-1494|
|Howe, B J; Cooper, M E; Wehby, G L et al. (2017) Dental Decay Phenotype in Nonsyndromic Orofacial Clefting. J Dent Res 96:1106-1114|
|Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2017) Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate. Am J Med Genet A 173:1531-1538|
|Roosenboom, Jasmien; Indencleef, Karlijne; Hens, Greet et al. (2017) Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting. Am J Med Genet A 173:2886-2892|
|Ruegg, Teresa A; Cooper, Margaret E; Leslie, Elizabeth J et al. (2017) Ear Infection in Isolated Cleft Lip: Etiological Implications. Cleft Palate Craniofac J 54:189-192|
|Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2017) Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Hum Genet 136:275-286|
|Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor et al. (2017) Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing. Birth Defects Res 109:1030-1038|
|Lee, Myoung Keun; Shaffer, John R; Leslie, Elizabeth J et al. (2017) Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2. PLoS One 12:e0176566|
|Liu, Huan; Leslie, Elizabeth J; Carlson, Jenna C et al. (2017) Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting. Nat Commun 8:14759|
Showing the most recent 10 out of 107 publications