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2016 X01 Projects Abstracts

Project Number:1 X01 HL136998-01Contact PI / Project Leader:Wendy K. Chung
Title:Genomic Analysis of Congenital Diaphragmatic Hernia and Associated Congenital AnomaliesAwardee Organization:Columbia University Health Sciences

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 families and health care providers 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 congenital anomalies 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 and define new genes and conditions associated with CDH by performing whole genome sequencing on parent child trios and RNA sequencing of diaphragm tissue in a clinically well characterized cohort to identify rare de novo mutations and inherited 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 to guide clinic decisions. 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.

 

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 FamiliesAwardee 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

 

Project Number:1 X01 HL136997-01Contact PI / Project Leader:John M. Maris 
Title:Genetic basis of neuroblastoma initiation and progressionAwardee Organization:Children's Hospital of Philadelphia

Abstract:

DESCRIPTION (provided by applicant): 

Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The long-term goal of our research program is to ultimately improve neuroblastoma cure rates by first comprehensively defining the genetic basis of the disease. The central hypothesis to be tested here is that neuroblastoma arises largely due to the epistatic interaction of common and rare heritable DNA variation. Here we will perform a comprehensive whole genome sequencing of 563 quartets of neuroblastoma patient germline and diagnostic tumor DNAs and germline DNAs from both parents. The case series was recently collected through a Children's Oncology Group epidemiology clinical trial and is robustly annotated with complete demographic (age, sex, race, ethnicity), clinical (e.g. age at diagnosis, stage, risk group), epidemiologic (parental dietary and exposure questionnaire) and biological (e.g. tumor MYCN status and multiple other tumor genomic measures) co- variates. Subjects were consented for genetic research and DNA is immediately available for shipment for sequencing. We propose Illumina-based whole genome sequencing in the 563 trio germline samples (Aim 1; due to missing parent: 465 neuroblastoma triads, 94 child-mother dyads and 4 father-child dyads = 1591 whole genome sequences) and matched diagnostic tumor DNA (Aim 2; N=484). We propose at least 100x average sequencing depth for these 2075 DNA samples in order to have sufficient sequencing coverage to reliably identify and quantify germline mosaicism and somatic subclonal heterogeneity. We will use our established analytic pipeline that is currently being used to study the germline genomes of all cases sequenced through the NCI supported Therapeutically Applicable Research to Generate Effective Treatments program. We plan a three stage analytic approach, first focusing on classic de novo and inherited Mendelian damaging alterations. We will next integrate our extensive epigenomic data from human neuroblastoma cell lines and genome-wide association study data (N=5,703 neuroblastoma cases to date) to guide a comprehensive assessment of noncoding variants that influence tumor initiation with a recently established analytic pipeline. Finally, we will utilize the tumor DNA analyses to inform relevance via somatic gain or loss of function effects at the sequence and/or copy number levels. All data generated in this project will be immediately placed into the Genomic Data Commons (GDC) and we will compute within this environment by importing our analytic pipelines into the GDC. These data will be fully integrated into the Kids First Data Resource and freely shared with all academically qualified petitioners. This comprehensive data set derived from a large and richly phenotyped series of neuroblastoma DNA quartets will be integrated with existing germline and/or tumor genomic data from over 6,000 neuroblastoma subjects (but none with matched patient-parent germline sequencing data) to provide an unparalleled opportunity to comprehensively discover the genetic basis of neuroblastoma. PUBLIC HEALTH RELEVANCE: The proposed research Program is relevant to public health because we are addressing a major gap in our understanding of the genetic basis of cancer, here focusing on neuroblastoma, a perplexing and often fatal pediatric malignancy. The proposed research Program is highly relevant to the NIH mission of improving health outcomes as we expect that discoveries of the basic genetic mechanisms of tumor initiation will lead to rational new clinical interventions.

 

Project Number:1  X01 HL136999-01 Contact PI / Project Leader:Charles G. Mullighan
Title:Genomic analysis of familial leukemiaAwardee Organization:St. Jude Children's Research Hospital

Abstract:

DESCRIPTION (provided by applicant): 

Acute lymphoblastic leukemia (ALL) is a precursor cell neoplasm and the commonest childhood cancer, and Hodgkin and non-Hodgkin lymphoma (HL) are forms of lymphoma that arise in both children and adults. Both are multi-genic diseases characterized by multiple subtypes and distinct constellations of somatic genetic changes. There is growing evidence for a genetic predisposition to both diseases, demonstrated by genome- wide association studies that have identified associations between common variants in transcription factors and tumor suppressors and ALL risk, subtype and outcome, and the identification of highly penetrant mutations in transcription factor and tumor suppressor genes in familial ALL. However, the landscape of germline predisposition variants that drive familial and sporadic hematological malignancies (HM) are unknown. In this study we will address this knowledge gap by performing whole genome sequencing of kindreds with familial, coupled with recurrence screening of extended cohorts of ALL and HL and integration of germline and somatic data. We have collected over 60 familial HM kindreds that will be subjected to tumor and germline whole genome sequencing (WGS) supported by this grant mechanism (Specific Aim 1). We will examine the frequency of novel variants, and mutations in newly identified genes, in large cohorts of sporadic ALL/HL (Specific Aim 2, funded separately) and examine associations between germline mutations in familial and sporadic ALL and clinical, pathologic and somatic genomic features (Specific Aim 3, funded separately). The project will be conducted by a group of co-investigators at St Jude Children’s Research Hospital with complementary expertise in clinical genetics (Nichols, Kesserwan), germline predisposition (Yang, Mullighan), clinical aspects of ALL and HL (Sandlund, Metzger) and computational approaches (Rampersaud). We have established collaborations with the COG and assembled the recurrence testing cohorts. Many of the familial tumor and germline samples are in hand, with acquisition of relative material ongoing to submit samples for sequencing by study activation. Together, this represents a logical framework to comprehensively dissect the interaction of germline and somatic genetic alterations in HM, and will provide important mechanistic insights, opportunity for clinical translation, and an invaluable public resource of genomic data. PUBLIC HEALTH RELEVANCE: (RELEVANCE STATEMENT) Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and a leading cause of cancer death in children, adolescents and young adults. Hodgkin and non-Hodgkin lymphoma are also important hematologic malignancies (HM) that occur in children. Each are genetic diseases with growing evidence for a germline predisposition of both familial and sporadic cases, however the inherited genetic basis of ALL/lymphoma are poorly understood. Such knowledge is essential to gain mechanistic insight into the basis of tumor formation, and to guide genetic counseling and genetic management. Here we have assembled an unmatched group of basic genomic, computational and clinical investigators with an interest in the genetics of HM, a large collection of familial HM kindreds, and extended recurrence cohorts of ALL and HL which will be used to identify the genetic basis of familial HM, examine the frequency of germline variants in sporadic ALL and HL, and to integrate inherited and somatic genomic data. These studies have high potential to provide fundamental new insights into the inherited genetic basis of HM, to provide important information to guide clinical management, and to provide an invaluable public resource of genomic data.

 

Project Number: 1  X01 HL136994-01 Contact PI / Project Leader:Sharon E. Plon
Title:Identifying novel cancer susceptibility mutations from unselected childhood cancer patient and parent triosAwardee Organization:Baylor College of Medicine

Abstract:

DESCRIPTION (provided by applicant): 

Genome-scale sequencing methods have allowed studies that demonstrate that approximately 10% of patients carry germline pathogenic variants in a wide spectrum of known cancer susceptibility genes. These results also highlight that our very limited ability to predict which patients are likely to carry a cancer susceptibility mutation based on tumor type and family history. In addition, prior projects have (1) focused on findings in known germline cancer genes, limiting new discovery, and (2) performed the sequencing on the cancer patient without parental samples obviating our ability to systematically determine the underlying genetic mechanisms such as de novo mutations. In this proposal, we describe whole genome sequencing (WGS) of patient germline and parental samples including the tumor sample when available from an unselected racially and ethnically diverse cohort of well phenotyped pediatric cancer patients enrolled in the NIH supported Baylor Advancing Sequencing in Childhood Cancer Care (BASIC3) trial. Based on the detailed medical record extraction we have identified that approximately 20% of this cohort also includes patients with a neurodevelopmental or structural anomaly. Data derived from this project should fill current gaps in our knowledge (1) the proportion and nature of pathogenic or likely pathogenic germline mutations in known cancer genes that are missed by more standard proband only whole exome sequencing methods and (2) identification of new cancer susceptibility genes to better define the underlying structure of pediatric cancer susceptibility, particularly, when data generated by this project is combined with other Gabriela Miller Kids First and TARGET sequencing in the NCI Data Commons. PUBLIC HEALTH RELEVANCE: We describe whole genome sequencing of pediatric cancer patient (n=120) germline and parental samples including the tumor sample when available from an unselected racially and ethnically diverse cohort of well phenotyped solid tumor (CNS and non-CNS) cancer patients. Data derived from the WGS described here should provide substantial new data to define the underlying genetic structure of cancer susceptibility to pediatric cancer.

 

Project Number:1  X01 HL132375-01A1 Contact PI / Project Leader:Jonathan Rios
Title:Genomics of Orthopaedic Disease ProgramAwardee 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.
Sequence and clinical data released in dbGap: Accession Number: phs001410.v1.p1

 

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 DefectsAwardee 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.
Sequence and clinical data released in dbGap: Accession Number: :phs001138

 

Project Number:X01 HL132380-01A1 Contact PI / Project Leader:Jun Shen
Title:Hear-n-Seq: Sequencing Kids First for HearingAwardee Organization:Brigham and Women's Hospital

Abstract:

DESCRIPTION (provided by applicant): 

With hearing loss of 40 decibels or more and 1 in 100 children will lose significant hearing by school age, making it one of the single most common structural defects affecting the pediatric population. Hearing loss can affect a child's ability to develop speech, language, cognitive and social skills. The earlier a child with hearing loss starts receiving appropriate medical and educational services, the more likely they are to reach their full potential. More than half of early hearing loss is due to genetic factors. Approximately 1 in 500 babies is born While the majority of prelingual hearing loss is nonsyndromic, over 400 syndromes have been described that have hearing impairment as a component. It is critically important to identify the etiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Genetic testing is available for congenital hearing loss, but the current standard of care is by no means comprehensive because: 1) many types of genetic variants in known hearing loss genes are not detectable by clinical testing, and 2) it is estimated that more than 100 hearing loss genes are as yet unknown. With this proposal called Hear-'n-SEQ, we will leverage the resources of the NIH Common Fund's Gabriella Miller Kids First Pediatric Research program to"seek-out" the genetic etiology of childhood hearing loss through comprehensive phenotypic and genomic analyses in an international cohort of hearing impaired patients. By sharing both the clinical and sequence data with the pediatric research community we will be empowered to identify genetic pathways that underlie hearing loss as well as pathways shared with other pediatric conditions. This project will be coordinated through the Harvard Medical School Center for Hereditary Deafness (HMSCHD). The Specific Aims of the project are to: (1) build an international consortium to identify and collect well-curated patient clinical information and DNA samples from children with hearing loss and their parents (trios) or carefully selected multiple affected individuals based on the pedigree structure, (2) submit appropriate DNA samples for whole genome sequencing at an NIH-supported sequencing center, and, (3) identify the genetic etiology of hearing impairment in individuals where possible, and integrate the data collectively into a shared data resource. Because of the tremendous genetic heterogeneity inherent in hearing loss, the proposed international collaboration will produce a maximum yield of diverse genetic causes, as it has been well established that different populations segregate distinct concentrations of hearing loss alleles. Therefore we will sample the hearing impaired pediatric populations of parts of Asia (Hong Kong), the Middle East (Turkey), and the US (individuals of European, African American, Central American and Caribbean descent). In addition to identifying novel etiologies for hearing loss, ultimately this work is designed to help create a pipeline for routinely integrating genomic sequencing into clinical diagnostics, generating more refined diagnostic capabilities, and ultimately more targeted therapies or interventions for children with hearing loss. PUBLIC HEALTH RELEVANCE: Hearing loss is the most common structural birth defect detected through newborn screening. Genetic factors contribute to the majority of childhood hearing loss, but currently available genetic testing can only identify the cause in 1/3 of patients. This Hear-'n-SEQ project proposes to use the latest DNA sequencing and comprehensive genetic analysis technologies to identify the genetic causes of previously unsolved hearing loss cases, with an overarching goal of offering better and timelier treatment options for children with hearing loss.

 

This page last reviewed on March 7, 2024