2016 X01 Projects Abstracts
2016 X01 Projects Abstracts
| Project Number: | 1 X01 HL136465-01 | Contact PI / Project Leader: | Mary L. Marazita |
| Title: | Kids First: Genomics of Orofacial Cleft Birth Defects in Latin American Families | Awardee Organization: | University of Pittsburgh |
Abstract:DESCRIPTION (provided by applicant):Nonsyndromic orofacial cleft birth defects (OFCs) are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. Before the advent of genomic approaches, evaluation of candidate genes revealed at best modest associations with a number of genes. By contrast, genome-wide linkage and association studies by our group and others have identified approximately 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs, which together account for about 55- 60% of the heritability for this disorder. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Part of the “missing heritability” for OFC may be accounted for by rare variants within regions of the genome associated with risk to OFC. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is identify specific OFC risk variants by performing whole genome sequencing (WGS) of Latin American OFC parent-case trios. Notably, Latin American families are at high risk of OFC. Statistical analyses of the WGS results will identify common and rare variants likely to be involved in OFC risk. The resulting data (genetic and phenotypic), analyses and other resources will be made available through dbGaP, the proposed Pediatric Data Resource of the Kids First Program (and/or other NIH-designated repositories). Additional goals of this project are beyond the scope of the Kids First Initiative, but include replicating risk variants identified by WGS in our large resource of OFC case families and controls, and validating expression and functional significance of replicated variants through our other existing collaborators who focus on animal models of OFC. Successful completion of the proposed specific aims will more fully illuminate the genetic architecture of OFC and will provide insight about the biological mechanisms underlying craniofacial development. Ultimately, this project will translate to improved risk prediction, treatment, and prognosis for individuals affected by OFCs. The specific aims are: (1) to identify risk variants for OFC by WGS of Latin American OFC case trios; (2) to make the WGS results available through the proposed Pediatric Data Commons and/or other NIH-designated repositories; (3) to do combined analyses with the WGW in White Trios (from our previous Kids First project); (4) replicate variants identified in the WGS of proband trios; and (5) to explore functional significance and expression of replicated results in cell lines and animal models. PUBLIC HEALTH RELEVANCE: Nonsyndromic orofacial cleft birth defects (OFCs) are very common structural birth defects caused by genetic factors, environmental exposures, and their interactions. The goal of the current study is to identify specific OFC risk variants by performing whole genome sequencing of Latin American OFC families. Successful completion of the project will more fully illuminate the genetic architecture of OFC, and will ultimately translate to improved risk prediction, treatment, and prognosis for individuals affected by OFCs. Sequence and clinical data released in dbGap: Accession Number: phs001420 |
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| Project Number: | 1 X01 HL132375-01A1 | Contact PI / Project Leader: | Jonathan Rios |
| Title: | Genomics of Orthopaedic Disease Program | Awardee Organization: | UT Southwestern Medical Center |
Abstract:DESCRIPTION (provided by applicant):Pediatric birth defects are a leading cause of pediatric hospitalizations and deaths. The Gabriella Miller Kids First initiative seeks to understand the genetic causes of pediatric birth defects by synergizing state-of-the-art genetic research techniques with detailed clinical assessments in children. In addition, the Kids First initiative will build a collaborative environment by making available genetic and clinical information that will foster collaborative research and ultimately improve our understanding of pediatric birth defects. At Texas Scottish Rite Hospital for Children, the Genomics Of Orthopaedic Disease (GOOD for Kids) program similarly seeks to understand pediatric birth defects, such as adolescent idiopathic scoliosis (AIS), through close interaction and collaboration with orthopaedic surgeons and treating physicians. AIS is a debilitating curvature and rotational deformity of the spine and is the most common pediatric musculoskeletal deformity in the world. Our long- term goal is to improve management and prevention of AIS by discovering genetic and developmental risk factors leading to spine deformity. Our collaborative research team has extensive experience and expertise with gene discovery using next-generation sequence analysis, and we have led the field in identifying genetic risk factors for AIS. To expand on our previous successes, we propose to perform whole-genome sequencing (WGS), the most comprehensive approach to identify genetic causes of pediatric disease, using a tiered approach. In our first tier we propose sequencing families with multiple generations of relatives with AIS. These families provide the greatest power to identify new genes when faced with the vast amounts of data generated by WGS. This approach is supported by detailed clinical characterization and rich histories for families that, in some cases, were treated for multiple generations at our Institutions. Our unique ability to perform WGS analysis in multiple affected family members segregating AIS through multiple generations allows us to identify new genetic causes of AIS despite reduced penetrance of the disease. We also propose Tier 2 families, which include those with affected siblings with AIS but without affected parents and no evidence for dominant inheritance. Recognizing reduced penetrance in AIS, our multi-faceted approach to WGS analysis will include analyses for recessive disease as well as dominant disease with non-penetrant parents for Tier 2 families. Candidate genes identified in each Tier will be validated by re-sequencing, evidence of association from our current GWAS meta-analysis, and individual variant association testing in our singleton collection of >2500 cases with AIS. Our approach is supported by our access to extensive clinical characterization and documentation for each study subject, our close collaboration with referring physicians, and our considerable experience and commitment to genetic analysis of AIS. Together, the power of our clinical and genomic analyses will meet the goals of the Kids First initiative, will expand our understanding of pediatric musculoskeletal disease, and may lead to better diagnosis and treatments for children with AIS. PUBLIC HEALTH RELEVANCE: The Kids First initiative seeks to perform whole-genome sequencing in pediatric patients with birth defects and to merge this genetic information with detailed clinical evaluations, all with the goal of improving our understanding of pediatric birth defects and improving treatment in children. We propose the Genomics Of Orthopaedic Disease (GOOD For Kids) program that will expand our current efforts to understand the genetic etiology of adolescent idiopathic scoliosis (AIS), the most common pediatric musculoskeletal deformity in the world. Our collaborative group has led the field in identifying genetic risk factors for AIS, and, with the Kids First initiative, promises to continue making strides to understand the genetic mechanisms causing disease and hopefully improve diagnosis and care of these children. |
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| Project Number: | 1 X01 HL136976-01 | Contact PI / Project Leader: | Christine E. Seidman |
| Title: | Discovery of De Novo and Inherited Mutations that Cause Prevalent Birth Defects | Awardee Organization: | Harvard Medical School |
Abstract:DESCRIPTION (provided by applicant):The Pediatric Cardiovascular Genetics Consortium (PCGC) proposes to define genetic causes for congenital heart defects (CHD) as part of the Gariella Miller Kids First Pediatric Research Program. CHD is the most common birth defect and is often accompanied by another congenital anomaly (CA). The PCGC has recruited and clinically characterized ≥ 10,000 CHD probands and parents (CHC trios), including 30% probands with CHD + CA. From extensive exome sequence (WES) analyses in over 2000 CHD trios, genome sequence (WGS) analyses of 50 CHD trios, and other genetic studies, we identified a substantial enrichment of damaging de novo mutations in developmental genes that modulate embryonic transcription. Based on these discoveries, we hypothesize that PCGC probands with uninformative genomic analyses (WES-negative) carry mutations in critical regulatory elements that participate in developmental expression of cardiac genes. To identify these etiologies, we propose analyses of WGS in 500 prioritized WES-negative CHD trios that include probands with banked CHD tissues (n=278), one damaging variant in a recessive CHD gene (n=186), and older fathers (n=60; age>45). We will capitalize on existing RNAseq data from CHD tissues, DNA methylation studies and the extensive computational and functional data on cardiac enhancers provided by our collaborating investigators, to analyze coding and non-coding, SNVs and SVs. We will use existing resources and capabilities of the PCGC and its companion consortium in the Bench to Bassinet Program, the Cardiovascular Development Consortium, to perform confirmatory functional genomics studies using cell and animal models outside of the GMKF program. We expect that these studies will provide novel insights into the molecular basis for birth defects and fundamental knowledge about genes and pathways involved in the development of the heart and other organs. Our aims are to: 1. Define de novo and transmitted variants, both SNVs and SVs, that cause dominant, recessive, and sporadic CHD ± CA. 2. Identify pathogenic de novo and transmitted variants in coding and regulatory regions both by case- control analyses and orthogonal data sets (ENCODE, cardiac enhancers, promoters, and regulatory ncRNAs, genes with unexplained loss of expression or allelic-specific expression in CHD tissues, and genome-wide DNA methylation data). PUBLIC HEALTH RELEVANCE: Through the use of whole genome sequencing of individuals with congenital heart disease (CHD) and other congenital malformations, and their unaffected parents, this project will drive discovery of the genetic causes for common birth defects. The new insights gained from this project will improve care by enabling DNA diagnostics for birth defects and by providing novel mechanistic insights, with which new therapies can be developed. |
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