Genetic Factors in Birth Defects

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

DNA has been obtained from approximately 20 major malformations for current and future investigations. We have recently expanded our investigations to include searching for copy number variants in rare defects. New York has an exceptionally valuable research resource in having approximately 250,000 births per year from which to identify children with rare defects. In addition to classic candidate gene approaches, cases have been selected for copy number variant studies. Our collaboration with the CDC's National Birth Defects Prevention Study and Dr. Paul Romitti at the University of Iowa is currently examining genetic data for associations with choanal atresia, a defect in which the nasal passages fail to develop normally. This study involves testing samples from New York State and from the collaborative group that formed the National Birth Defects Prevention Study. Other defects currently being studied include oral clefts, hypertrophic pyloric stenosis and craniosynostosis. The previous work focused on saggital craniosynostosis. These collaborations expand on this to look for genetic factors associated with defects in other sutures. This work has received external funding and is ongoing. We have established a collaboration with the Statens Serum Institut in Copenhagen, Denmark to examine genetic factors in congenital hydrocephalus. Laboratory analysis is complete and the interpretation of the results has begun. We will also collaborate with the University of Iowa to examine genetic risk factors in club foot. We finished a study with the University of Iowa to examine risk factors in oral cleft cases. Orofacial clefts (OFCs) are the most common birth defects in the head and neck region, affecting 1 out of every 700 live births worldwide. A total of 70% of the OFCs are classified as non-syndromic with no visible recognizable structural defects other than clefts. Syndromic clefts account for 30% of the OFCs, where there is a consistently defined structural anomaly in addition to clefts. In terms of etiology, OFCs are complex traits, with genetic, environmental and stochastic factors contributing to the phenotypic expression. To date, 6 genome-wide association studies (GWASs) and 3 meta-analysis for cleft lip with or without cleft palate (CL/P) and 3 GWASs for cleft palate only (CPO) have been conducted, and over 40 risk loci have been identified. All of these studies have been conducted in individuals of European and Asian ancestry, with this study representing the first GWAS in Africans. African populations represent novel and richly productive populations for genetic and environmental exposure studies for OFC because they have the greatest genetic diversity of any continental population. As part of a large consortium, we conducted genome-wide association analyses for cleft palate only (CPO) and cleft lip with or without palate (CL/P) with 17 million markers in sub-Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice showed expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously reported 8q24 was the most significant locus for CL/P in our study, and we replicated several previously reported loci including PAX7 and VAX1. This first GWAS of OFC in sub-Saharan Africans identified novel loci for CPO and confirmed several findings previously reported from other ancestral populations. These findings add to the growing evidence about genetic risk factors for OFC and provide new candidate genes for functional studies. As part of our collaboration with the Danish Statens Serum Institut, we performed a genome-wide meta-analysis to identify new loci associated with infantile hypertrophic pyloric stenosis. Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of 2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 odds ratio (OR) = 2.32; P = 3.0 10-15, is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.