Genetic Epidemiology Of Craniofacial Disorders

  • Diehl, Scott (PI)
  • Diehl, null S. R. (CoPI)
  • Diehl, S S.R (CoPI)

Project Details


Clefts of the lip and palate (CLP) are one of the most common craniofacial anomalies, with a rate of 1:650 in the United States population. Over 250 genetically based syndromes exist which include cleft lip or palate as a feature of their clinical presentation. Since the fall of 1993, we have been collaborating with the Lancaster Cleft Palate Clinic in Lancaster, PA. This project is a large-scale molecular epidemiological study, involving the comprehensive mapping of highly informative DNA markers, utilizing the clinical population from the Lancaster Cleft Palate Clinic and affiliated clinics. We also completed recruitment efforts at Washington University, St. Louis and at the University of North Carolina, Chapel Hill. Semiautomated gene mapping technologies developed by our group in ongoing CLP studies are being applied to map genes responsible for clefting. We are currently completing statistical analyses of both our genome scan and candidate region gene single nucleotide polymorphism (SNP) mapping data. Two analytical strategies are being employed: case-sibling control analysis to evaluate gene-disease associations and gene-environment interactions, and linkage disequilibrium and linkage analyses to identify chromosomal locations associated with susceptibility to non-syndromic oral clefts. Candidate genes and chromosomal regions that have been tested using this approach include SNPs and flanking markers for Methylenetetrahydrofolate Reductase on chromosome 1. In a reanalysis of previously published data from a study of this SNP, we found that multivitamin use appeared to protect against non-syndromic oral clefts. We also are studying SNPs at the Transforming Growth Factor Alpha and Alcohol Dehydrogenase 3 genes located on chromosome 2, MSX1 on chromosome 4p, regions on 4q where possible linkage and a deletion associated with clefting have been reported, F13A on chromosome 6, Transforming Growth factor Beta 3 on chromosome 14, D17S579, BCL3 on chromosome 19, and D22S264. Environmental risk factors that will be included in the models are maternal use of tobacco, alcohol, multivitamins and medications, diseases during pregnancy, and family history of any birth defect. The linkage disequilibrium and linkage analyses component of this research effort involves use of numerous complex statistical methods applied to the candidate genes and chromosomal regions as well as all genome scan marker loci. These methods include Transmission Disequilibrium Tests (TDT) on case-parent triads, two-point sib-pair analyses, with covariates, with and without constraints, non-parametric linkage analysis for extended pedigrees, and two-point and multipoint LOD score analysis, including the admixture test for linkage in the presence of locus heterogeneity. Van der Woude syndrome is an autosomal dominant craniofacial disorder with high penetrance and variable expression of its clinical features of cleft lip and/or cleft palate, lip pits and hypodontia. A gene which causes this disease has been localized to a < 2 cM region on the long arm of chromosome 1q32. All VWS families studied previously are linked to this region (i.e., locus homogeneity). The aim of our study was to refine the localization of the VWS gene and to further assess possible locus heterogeneity. We recruited four multiplex VWS families in collaboration with Drs. Mazaheri and Long of the Lancaster Cleft Palate Clinic, Dr. Soraya Beiraghi of the University of Nebraska Medical Center and Dr. Robert P. Erickson of the University of Arizona Health Science Center. We used automated genotyping methods to characterize 19 STR markers on chromosome 1 in the VWS candidate gene region. We performed two point and multipoint LOD score analyses using a high penetrance autosomal dominant model. All families show positive LOD scores without any recombination in the candidate region. The largest two point LOD score was 5.87. Our results are fully consistent with previous mapping of the VWS gene between D1S491 and D1S205. Our assay method for STR markers provided highly accurate size estimation of marker allele fragment sizes and, therefore, enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the U.S. This suggests the possibility of a unique origin for a mutation responsible for many or most cases of VWS. If confirmed in other families, linkage disequilibrium may be helpful for fine mapping of the location of the VWS disease gene to facilitate its cloning. In collaboration with Dr. Robert P. Erickson of the University of Arizona Health Sciences Center, we statistically analyzed a teratogen-induced mouse model of oral cleft susceptibility using recombinant inbred lines and genetic markers covering the entire mouse genome. A new statistical method for gene mapping of discrete traits (affected versus unaffected) was developed for this study, analogous to Quantitative Trait Locus (QTL) mapping of continuous traits. Several chromosomes and genes were identified that can now be used as candidates for evaluation in humans. These data also suggest that some genes influence both cleft lip and cleft palate susceptibility. We participated in the development of guidelines for the design and analysis of studies on non-syndromic cleft lip and cleft palate, conducted under the auspices of the International Consortium for Oral Clefts Genetics.
Effective start/end date10/1/939/30/02


  • National Institute of Dental and Craniofacial Research


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