FY15 X01 Projects for the Gabriella Miller Kids First Program

Project Number: 1 X01 HL 132366-01 Contact PI / Project Leader: Wendy K. Chung 
Title: Genomic Analysis of Congenital Diaphragmatic Hernia Awardee Organization: Columbia University Health Sciences
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH) is defined as a defect in the muscular or tendinous portion of diaphragm that results in antenatal herniation of the abdominal contents into the thoracic cavity and pulmonary hypoplasia due to compression of the lungs. The incidence of CDH is 1 in 3000 live births, accounting for 1- 2% of infant mortality and 8% of all birth defects, making it one of the most common and lethal congenital anomalies. CDH is isolated in 50-60% of cases but is associated with other major anomalies, most commonly congenital heart disease or central nervous system malformations, in the remaining 40-50%. Historically CDH carried a grave prognosis with mortality of greater than 50%. However, with recent advances in the post-natal care of children with CDH, survival has improved significantly. However, with improved survival, many of the long term morbidities of CDH have been exposed including pulmonary hypertension, the leading cause of CDH morbidity and mortality. In addition, a subset of children with CDH demonstrate significant developmental delay and intellectual disabilities. Many parents and prospective parents seek prognostic clinical information about other associated birth defects or genetic syndromes, but prognostic data are extremely limited unless a chromosomal anomaly is identified. The etiology of CDH is largely unknown. Evidence is accumulating that many birth defects can result from copy number variants, de novo mutations, and inherited rare mutations, often unique to the family. We propose to elucidate the underlying genomic architecture of CDH by performing whole genome sequencing on parent child trios and RNA sequencing of diaphragm tissue in a clinically well characterized cohort to identify de novo mutations and inherited rare variants. Our long-term goal is to define a set of genes important in the etiology of CDH and characterize new clinical syndromes associated with CDH. We believe this information will improve genetic diagnostic methods and provide more accurate clinical prognostic information. PUBLIC HEALTH RELEVANCE: Congenital diaphragmatic hernia (CDH) is a serious birth defect accounting for 1-2% of infant mortality and 8% of all birth defects. We propose to elucidate the underlying genomic architecture of CDH by performing whole genome sequencing and RNA sequencing on diaphragm tissue to characterize new clinical syndromes associated with CDH to provide more accurate clinical prognostic information.

Sequence and clinical data released in dbGap: Accession Number: phs001110

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Project Number: 1 X01 HL 132377-01 Contact PI / Project Leader: Elizabeth C. Engle 
Title: BCH Structural Birth Defects Collaboration: Syndromic cranial dysinnervation disorders Awardee Organization: Children’s Hospital Corporation
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Abstract: DESCRIPTION (provided by applicant): It is estimated that approximately 1 of every 33 infants in the United States is born with a birth defect. Among these, the subset associated with inability to move the eyes and face cause significant disability, are frequently accompanied by additional structural birth defects, and often segregate within families or arise from de novo mutations. The applicant's genetic and developmental studies have led to the definition of these syndromes as a new category of human disease referred to as the `congenital cranial dysinnervation disorders' (CCDDs). The applicant has defined multiple CCDD syndromes, uncovered their genetic etiologies, and determined that these disorders often result from maldevelopment of cranial motor neurons and their axonal processes. Despite the many CCDD genes and pathways identified by the applicant, many families remain genetically undefined. Thus, the goal of this proposal is to generate and interpret whole genome sequence (WGS) data to identify previously undefined genetic causes of CCDDs and related anomalies. WGS will allow the detection of non-coding variants, CNVs, and complex rearrangements, while also providing better coverage of coding regions than exome sequencing, thus filling a gap of information obtained by other genetic approaches. We have chosen DNA samples for WGS from a large and unique cohort of deeply phenotyped research participants, many of whom have associated findings and multiple organ involvement. The DNA samples have been screened for mutations in the known CCDD genes and many have had whole exome sequencing (WES), yet remain genetically unsolved. The participants have consented to sharing of WGS and relevant phenotype data through an NIH-approved controlled-access repository, and almost all have consented to recontact, permitting us to collect additional phenotyping data and samples, reconsent when necessary, and to discuss enrollment in additional studies. Because a barrier to informative discovery from WGS is proper data analysis, these data will be analyzed in collaboration with leaders in genetics and genomics at the Broad Institute of MIT and Harvard and at the Boston Children's Hospital, and in collaboration with CCDD researchers at Mount Sinai Medical Center and NIH. These joint analyses should greatly improve the quality and interpretation of the genome data generated, and significantly increase our likelihood of identifying multiple new genetic etiologies or CCDDs and their associated anomalies. As part of this grant mechanism, the WGS and phenotype data will become part of the integrated NIH Pediatric Research Data Resource and the applicant will also participate in development of the Kids First Data Resource Consortium. This will be followed by functional studies to further uncover CCDDs mechanisms and shared pathways among CCDDs and between CCDDs and other structural birth defects, and should lead to refined diagnostic capabilities and improved therapies. PUBLIC HEALTH RELEVANCE: Congenital paralysis of eye and facial movements arise from structural birth defects, result in impaired vision, perturbed facial and speech communication, profoundly disturbed interpersonal interactions and self-esteem, and are often accompanied by additional anomalies of the nervous system and other organs. To determine their genetic causes, DNA samples from a large cohort of research participants will be submitted for whole genome sequencing, and the data analyzed by a team of researchers at Boston Children's Hospital, the Broad Institute of MIT and Harvard, Mount Sinai Medical Center, and National Institute of Health. As part of this grant mechanism, these data will become part of the integrated NIH Pediatric Research Data Resource and the applicant will participate in the Kids First Data Resource Consortium.

Sequence and clinical data accessible through dbGaP: Accession Number: phs001247

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Project Number: 1 X01 HL 132363-01 Contact PI / Project Leader: Mary L. Marazita 
Title: Genomic Studies of Orofacial Cleft Birth Defects Awardee Organization: University of Pittsburgh
Abstract Text:

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 OFC parent-case trios. 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 the proposed Pediatric Data Commons 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 OFC case trios; (2) to make the WGS results available through the proposed Pediatric Data Commons and/or other NIH-designated repositories; (3) to replicate variants identified in the WGS of proband trios; and (4) 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 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 accessible through dbGaP: Accession Number:phs001168 

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Project Number: 1 X01 HL 132378-01 Contact PI / Project Leader: Kenan Onel 
Title: An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma Awardee Organization: The University of Chicago
Abstract Text:

Abstract:  DESCRIPTION (provided by applicant): For children with osteosarcoma, it has long been known that response to chemotherapy as measured by percent necrosis at the time of definitive surgery is a powerful prognostic biomarker. Patients with 90 percent or more tumor necrosis are likely to be cured of their disease, whereas those with less than 90 percent tumor necrosis are at high risk for treatment failure. Despite its clinical importance, however, virtually nothing is known about the genetic and molecular basis of this phenomenon. Consequently, there have been few advances in the treatment of osteosarcoma in decades. In this proposal, we will perform whole genome sequencing on serial samples obtained over time from a set of 198 patients with osteosarcoma, all treated similarly, and for whom we have complete clinical information. Of these patients, 52 have suffered a relapse of their disease. Our primary objective is to determine whether there are recurrent mutations in these relapse samples that may point towards common mechanisms of treatment failure, and may, therefore, suggest novel therapies for relapsed osteosarcoma. Our secondary objective is to determine the genetic drivers of treatment failure in osteosarcoma by analyzing within each patient the evolving spectrum of mutations selected by chemotherapy exposure over time. To our knowledge, this is the largest set of matched pre-therapy, post- therapy, and relapse samples ever assembled for any cancer. If successful, this project sets the stage for future functional studies exploiting our genetic findings to investigate the mechanisms of drug resistance in osteosarcoma. Perhaps more importantly, it also holds forth the promise of changing the paradigm for therapy in osteosarcoma, a disease that has thus far proven refractory to innovative therapies to improve the dismal survival of children with tumors that respond poorly to current chemotherapy protocols. PUBLIC HEALTH RELEVANCE: Although the survival of children with relapsed osteosarcoma is very poor, little is known about the etiology of treatment failure in this disease. The purpose of this project is to perform whole genome sequencing on serial samples from patients with osteosarcoma obtained before treatment, after treatment, and at relapse in order to identify the mutations and pathways that are drivers of drug resistance. If successful, our results may help identify patients at high risk for treatment failure and may yield new treatments for children who cannot currently be cured.

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Project Number: 1 X01 HL 132385-01 Contact PI / Project Leader: Joshua D. Schiffman 
Title: Genetic Contribution to Ewing Sarcoma in 330 parent-Offspring Trios Awardee Organization: University of Utah
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Abstract: DESCRIPTION (provided by applicant): Ewing sarcoma (ES) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identifid. ES has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with ES. Furthermore, neuroectodermal tumors appear to occur more commonly in families with ES. The two consistent epidemiology findings in ES include a very strong Caucasian predilection and increased rates of hernia in ES patients and their family members. Finally, the role of genetic microsatellite repeats in ES tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The Children's Oncology Group (COG) Study AEPI10N5 ("Genetic Epidemiology of Ewing Sarcoma") was begun to collect germline DNA from ES parent-offspring trios to explore the genetic risk for disease development. Each trio contains germline DNA and has been well characterized through a complete medical and family history evaluation. As part of the Gabriella Miller Kids First Pediatric Research Program, we will submit 330 ES trios from AEPI10N5 for whole genome sequencing (WGS). The study goals of this Kids First proposal include (1) To identify cancer predisposition genes in ES trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in ES trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in ES trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. All of the WGS and phenotype data from this study will be deposited into the designated data repository for the Kids First Common Fund and will be accessible to other researchers. The WGS of these 330 ES trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment. PUBLIC HEALTH RELEVANCE: Ewing sarcoma (ES) is a deadly pediatric bone cancer striking children and adolescents. We will submit 330 ES trios for whole genome sequencing (WGS) as part of the Gabriella Miller Kids First Pediatric Research Program. The ES trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to ES and the sequence data with be shared in a repository designated by the Kids First Common Fund.

Sequence and clinical data accessible through dbGaP: Accession Number: phs001228

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Project Number: 1 X01 HL 132370-01 Contact PI / Project Leader: Christine E. Seidman 
Title: Discovery of the Genetic Basis of Structural Heart and Other Birth Defects Awardee Organization: Harvard Medical School
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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 Gabriella 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 phenotyped ≥ 20,000 probands and parents (trios) with CHD, including 30% with CHD + CA. From exome sequencing and other genetic analyses, we discovered that CHD probands are enriched for damaging de novo mutations in developmental genes that modulate embryonic transcription. Based on these discoveries, we hypothesize that PCGC probands with uninformative prior genomic analyses will carry mutations in critical regulatory elements that participate in developmental gene expression. To identify these etiologies, we propose analyses of whole genome sequencing (WGS) of probands/unaffected parents trios, capitalizing on existing RNAseq data from CHD tissues, DNA methylation studies and the extensive expertise with cardiac enhancers of our collaborating investigators to inform prioritization of de novo non-coding, regulatory sequence variants. We will use 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. Our studies will provide novel insights into the genes and pathways involved in the development of the heart and other organs as well as into the clinical spectrum of birth defects. Our specific aims are: Aim 1. Select cohorts of CHD ± CA trios for WGS and rapidly provide high-quality DNA to the NIH- designated sequencing site. Aim 2. Identify de novo structural variants and variants that alter exome and splice sites. Aim 3. Identify de novo variants in CHD ± CA probands in non-coding regulatory elements. PUBLIC HEALTH RELEVANCE: Through the use of whole genome sequencing of individuals with congenital heart disease (CHD) and their unaffected parents, this project will drive discovery of the genetic causes of this class of birth defects, which will also have relevance for other types of congenital anomalies. 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.

Sequence and clinical data accessible through dbGaP: Accession Number:phs001138

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Project Number: 1 X01 HL 132384-01 Contact PI / Project Leader: Eric J. Vilain  
Title: Genetic Basis of Disorders/Differences of Sex Development (DSD) Awardee Organization: University of California Los Angeles
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Abstract: DESCRIPTION (provided by applicant): Disorders of Sex Development (DSD) are phenotypically heterogeneous, ranging from minor genital malformations (hypospadias, cryptorchidism, hypertrophy of the clitoris) to genital ambiguity. In the aggregate, DSD have an estimated incidence of about 1%. DSD can result in severe consequences for behavioral health, fertility, cancer risk and quality of life. For families, the birth of a child with a DSD, and the accompanying uncertainty about future psychological and sexual development, is believed to be extraordinarily stressful. Recently, the debate over clinical management of DSD, in particular gender assignment and genital surgery, has intensified; yet the scientific data on patient outcomes have remained very incomplete. Major obstacles to optimal clinical management of DSD include lack of outcome studies, but also a low genetic diagnostic yield, leading to gaps in the understanding of pathophysiology, and increasing the uncertainty around the clinical management of DSD. Here we propose to use the existing resource of the DSD Translational Research Network (DSD-TRN, PIs Vilain and Sandberg), a network of 10 clinical sites collecting standardized phenotypic information, banking DNA of patients with a DSD, and populating a Registry located at UCLA. We propose to perform Whole-Genome Sequencing (WGS) on 150 patients with DSD and their parents, as well as an additional 26 historical cases for which Whole-Exome Sequencing did not yield a causative variant, in order to investigate the following aims: Aim 1: To identify new exomic causes of DSD. Analysis of exomic variants is expected to yield causative variants in 35% of cases; Aim 2: To identify non exomic causes of DSD, with a three-prong approach: 2a- Specific search for variants within promoters and introns of known DSD genes, and in the promoters of genes for which WGS identified a variant in one exonic allele or a heterozygous structural variant; 2b- Search for de novo variants; and 2c- Search for large rearrangements (translocations, duplications, inversions); Aim 3: To identify the influence of environmental exposure on phenotypic variability of DSD. We will perform a systematic collection of environmental exposure by a comprehensive environmental questionnaire (NHANES) as well as NHGRI's PhenX tool kit and by modeling patient's environmental exposure using the family's geographical information. The environmental analysis will be focused on whether there are significant environmental differences between patients with a variant in the same gene and different degrees of phenotypic severity. The accessibility of a large sample of well characterized patients with DSD, and the collective expertise of our multidisciplinary team (medical genetics, statistics, computer science) increases the likelihood of a successful deciphering of causes of DSD and of improvement of outcomes for DSD. PUBLIC HEALTH RELEVANCE: A defining moment of our lives begins when we embark on a male or female path in the womb; disruption of typical male or female development results in Disorders/Differences of Sex Development (DSD), which occur frequently -- in about 1% of the human population. The quality of life of people affected by DSD and their families is often threatened by uncertainty about what caused the condition, leading to uncertainty about choices in care, and the chronic stress associated with experienced stigma and lifelong clinical care. To improve clinical care for patients with DSD and their families, we propose a study that uncovers the genetic causes of DSD by sequencing their entire genome.

Sequence and clinical data accessible through dbGaP: Accession Number: phs001178

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This page last reviewed on August 26, 2020