Oral clefts represent one of the most common congenital malformations, (occurring with birth prevalences between 1 and 2 per thousand). Despite extensive study, at both the epidemiologic and genetic levels, the etiology of oral clefts remains ill-defined. Studies have consistently shown strong familial aggregation of oral clefts, and Mendelian inheritance has been proposed. Recently, an association between risk to non-syndromic cleft lip +/- palate and a candidate gene (transforming growth factor a) has been described (Ardinger et al , 1989). A systematic search for effects of candidate genes is a logical extension of the current understanding of the genetics of oral clefts, and there are many such candidates (e.g. genes for growth factors and their receptors, genes for extracellular matrix proteins, homeobox genes, etc.). However, the design of such a study must also incorporate environmental risk factors, as there is evidence for a role of maternal exposures in the etiology of oral clefts. We propose: 1) to carry out an epidemiologic study of non-syndromic oral clefts simultaneously considering effects of candidate genes and environmental exposures. Cases for this study will come from a state wide survey of newborns with an oral cleft and 5 surgical treatment centers serving Maryland during the period 1993-1997. A population based sample of control infants will be drawn as a comparison group. An additional 250 cases and 250 controls from the Atlanta Birth Defects Risk Factor Surveillance Study will also be available, and parallel analyses will be done. Tests for potential risk factors will include standard maternal exposures, infant sex, etc., but will also consider effects of genotypes at candidate genes. Polymerase chain reaction (PCR) based methods will be used to type both case and control infants for markers at a series of candidate loci. 2) to carry out formal genetic analyses to identify the mode of inheritance of non-syndromic oral clefts and test for co-segregation with markers at these candidate loci in multiplex families.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010293-05
Application #
2331319
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1993-02-01
Project End
1999-07-31
Budget Start
1997-02-01
Budget End
1999-07-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Beaty, T H; Hetmanski, J B; Fallin, M D et al. (2006) Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations. Hum Genet 120:501-18
Mansilla, Maria Adela; Kimani, Jane; Mitchell, Laura E et al. (2005) Discordant MZ twins with cleft lip and palate: a model for identifying genes in complex traits. Twin Res Hum Genet 8:39-46
Wyszynski, Diego F; Albacha-Hejazi, Hasan; Aldirani, Mohammed et al. (2003) A genome-wide scan for loci predisposing to non-syndromic cleft lip with or without cleft palate in two large Syrian families. Am J Med Genet A 123A:140-7
Hwang, S J; Beaty, T H; McIntosh, I et al. (1998) Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency. Am J Med Genet 75:419-23
Wyszynski, D F; Zeiger, J; Tilli, M T et al. (1998) Survey of genetic counselors and clinical geneticists regarding recurrence risks for families with nonsyndromic cleft lip with or without cleft palate. Am J Med Genet 79:184-90
Wyszynski, D F; Duffy, D L; Beaty, T H (1997) Maternal cigarette smoking and oral clefts: a meta-analysis. Cleft Palate Craniofac J 34:206-10
Maestri, N E; Beaty, T H; Hetmanski, J et al. (1997) Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models. Am J Med Genet 73:337-44
Beaty, T H; Maestri, N E; Hetmanski, J B et al. (1997) Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992-1996. Cleft Palate Craniofac J 34:447-54
McIntosh, I; Clough, M V; Schaffer, A A et al. (1997) Fine mapping of the nail-patella syndrome locus at 9q34. Am J Hum Genet 60:133-42
Wyszynski, D F; Maestri, N; Lewanda, A F et al. (1997) No evidence of linkage for cleft lip with or without cleft palate to a marker near the transforming growth factor alpha locus in two populations. Hum Hered 47:101-9

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