2017 X01 Projects* for the Gabriella Miller Kids First Program

Contact PI Name

Institution Name

Title

Anticipated Number of Samples

Simeon Boyd

University of California Davis

Whole genome sequencing of nonsyndromic craniosynostosis

1140

 

Azeez Butali

University of Iowa

Whole Genome Sequencing of African and Asian Orofacial Clefts Case-Parent Triads

805

Wendy Chung

Columbia University Health Sciences

Genomic Analysis of Congenital Diaphragmatic Hernia and Associated Congenital Anomalies

815

Hakon Hakonarson

Children's Hospital of Philadelphia

Genetics at the Intersection of Childhood Cancer and Birth Defects

1788

Daniela Luquetti

University of Washington

Craniofacial Microsomia: Genetic Causes and Pathway Discovery

300

Joshua Schiffman

University of Utah

Expanded Ewing sarcoma cohort for tumor genomics and association with DNA repair deficiencies, clinical presentation, and outcome

785

Dawn Siegel

Medical College of Wisconsin

Genomic analysis of a cohort with infantile hemangiomas associated with multi-organ structural birth defects

300

Nara Sobreira

Johns Hopkins University

Genome-wide Sequencing to Identify the Genes Responsible for Enchondromatoses and Related Malignant Tumors

350

*All projects are pending sequencing completion

 

2016 X01 Projects* for the Gabriella Miller Kids First Program

Contact PI Name

Institution Name

Title

Anticipated Number of Samples

Wendy Chung

Columbia University Health Sciences

Genomic Analysis of Congenital Diaphragmatic Hernia and Associated Congenital Anomalies

942 + 15 (long read pilot)

Mary Marazita

 

University of Pittsburgh at Pittsburgh

Kids First: Genomics of Orofacial Cleft Birth Defects in Latin American Families

831 + 15 (long read pilot)

John Maris

Children's hospital of Philadelphia

Genetic Basis of Neuroblastoma initiation and progression

2154

Charles Mullighan

St. Jude Children's Research Hospital

Genomic Analysis of Familial Leukemia

483

Sharon Plon

Baylor College of Medicine

Identifying Novel Cancer Susceptibility Mutations from Unselected Childhood Cancer Patient and Parent Trios

371

Jonathan Rios

UT Southwestern Medical Center

Genomics of Orthopaedic Disease Program

300

Christine Seidman

Harvard Medical School

Discovery of De Novo and Inherited Mutations that Cause Prevalent Birth Defects

1275

Jun Shen

Brigham and Women's Hospital

Hear-n-Seq: Sequencing Kids First for Hearing

437

*All projects are pending sequencing completion

 

2015 X01 Projects for the Gabriella Miller Kids First Program

Contact PI Name

Institution Name

Title

Anticipated Number of Samples

Estimated Release Dates

Wendy Chung

Columbia University Health Sciences

Genomic Analysis of Congenital Diaphragmatic Hernia

600

Data Available through dbGap

Accession Number: phs001110

Elizabeth Engle

Children's Hospital Corporation

BCH Structural Birth Defects Collaboration: Syndromic cranial dysinnervation disorders

900

Late 2017

Mary Marazita

University of Pittsburgh

Genomic Studies of Orofacial Cleft Birth Defects

1242

Late 2017

Kenan Onel

The University of Chicago

An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma

400

TBD

Joshua Schiffman

University of Utah

Genetic Contribution to Ewing Sarcoma in 330 parent-Offspring Trios

1112

Late 2017

Christine Seidman

President and Fellows of Harvard College

Discovery of the Genetic Basis of Structural Heart and Other Birth Defects

900

Late 2017

Eric Vilain

University of California Los Angeles

Genetic Basis of Disorders/Differences of Sex Development (DSD)

300

Late 2018


FY17 X01 Projects for the Gabriella Miller Kids First Program

Project Number: N/A Contact PI / Project Leader: Simeon Boyd
Title: Whole genome sequencing of nonsyndromic craniosynostosis Awardee Organization: University of California Davis
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a common, major structural birth defect occurring in about 1 in 2,500 live births. About 85% of infants with CS present with nonsyndromic craniosynostosis (NCS) without associated birth defects or developmental delays. NCS is a heterogeneous condition with presumed multifactorial etiology and its causes remain largely unknown. Primary prevention strategies for NCS are limited. Our International Craniosynostosis Consortium (ICC) has advanced understanding of the genetic etiology for sagittal NCS (sNCS). Through our previous NIH-NIDCR funding (R01 DE016866), we successfully conducted the first genome-wide association study (GWAS) for sNCS and identified robust associations to loci near BMP2 and BBS9, both biologic plausible genes involved in skeletal development. A similar GWAS with 415 case-parent trios with metopic NCS (mNCS) is in progress, as is an additional GWAS of over 600 coronal NCS (cNCS) case-parent trios. Additionally, others reported that by whole exome sequencing (WES), SMAD6 mutations were found in 7% of probands in a cohort of sNCS, mNCS, or combined NCS cases. Importantly, among 17 NCS cases with SMAD6 mutations, 14 had T>C mutation (rs1884302) downstream of BMP2, suggesting a two-loci inheritance model. This discovery of an epistatic interaction between BMP2 and SMAD6 through use of GWAS and WES approaches explains only a small proportion of all NCS cases. Along with the data generated from the completed and ongoing GWAS’s, we believe that whole genome sequencing (WGS) is the next important step towards identifying causal variants in NCS cases, because it has the power to discover rare and common variants missed by other high- throughput technologies. We hypothesize that WGS will identify novel genetic factors beyond those identified with GWAS’s that contribute to the etiology of NCS. In this application, we propose to investigate 600 case- parent trios (200 cases each with sNCS, cNCS, and mNCS) and 20 multiplex families (11 with sNCS and 9 with mNCS) using WGS for discovery of all types of germline variants (de novo and inherited single nucleotide variants, insertions/deletions and structural variations). Somatic mutations contribute to the etiology of cancer and have been reported in some structural birth defects. Thus, we will perform WGS on 25 paired blood- derived and bone-derived DNA specimens obtained from sNCS probands for detection of somatic mutations. Our discovery specimen repository represents one of the largest collections compiled, and along with our extensive collection of independent specimens for future replication studies, represents an unparalleled resource for studying the genetic etiology of NCS. Given our past accomplishments, experienced interdisciplinary research team, and substantial resources, we are well-positioned to successfully complete the proposed research and provide critical insights into the multifactorial etiology of NCS. PUBLIC HEALTH RELEVANCE: Nonsyndromic craniosynostosis (NCS) is a common, major structural birth defect – due to the premature fusion of one or more cranial sutures – that requires extensive surgical correction and is associated with considerable ongoing medical problems and health care costs. Because little is known about the causes of NCS, whole genome sequencing will help advance knowledge of genetic factors contributing to the etiology of NCS. Sequencing data generated will lead to a better understanding of biological processes involved in the etiology of NCS and provide critical insights for development of early diagnostic tools and therapeutic strategies.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Azeez, Butali
Title: Whole Genome Sequencing of African and Asian Orofacial Clefts Case-Parent Triads Awardee Organization: University of Iowa
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): PROJECT SUMMARY Principal Investigators: Dr Azeez Butali is a tenure-track Assistant Professor at the Iowa Institute for Oral Health Research, College of Dentistry, and the University of Iowa. His primary research focus is on the genetics and epidemiology of complex traits including orofacial clefts. Dr Terri Beaty is a Professor at the John Hopkins University. Her research focus is on genetic epidemiology studies of several chronic diseases with complex etiologies, where both genetic and environmental risk factors control risk of disease. Co-investigators: Dr Adebowale Adeyemo is Deputy Director at the National Human Genome Research Institute. His focus is on the genetics and genomics of complex traits in African population. Dr Marazita is a Professor at the University of Pittsburgh. She is an expert in statistical genetics application for complex traits and identification of sub-clinical cleft phenotypes. Dr Cao is an Assistant Professor at the University of Iowa. He uses bioinformatics tools to interrogate the human genome and for analyses of gene-regulatory networks. Dr Ruczinski is a Professor at the John Hopkins University. His expertise is in statistical genetics, genomics and proteomics of complex traits. Dr Taub is an Assistant Scientist at the John Hopkins University. Her area of expertise is in genomics and statistical genetics for gene expression data, genotyping data and DNA methylation data Environment: The University of Iowa is a leading institution with a strong reputation for excellence in teaching, research and healthcare. The John Hopkins University is one of the leaders in the research, teaching and healthcare in the US. Both institutions are consistently amongst centers supported by NIH grants Research Study: The focus of this study is to identify novel risk variants for OFC in Africa and Asian OFC case-parent triads through analysis of Whole Genome Sequencing data. PUBLIC HEALTH RELEVANCE: TITLE: Whole Genome Sequencing of African and Asian Orofacial Case-Parent Triads The long term goal of this study is to identify specific genomic variants through WGS of OFC case-parent triads from African and Asian populations. The knowledge gained from these WGS studies will drive future research on OFC and should eventually lead to more effective interventions to reduce the risk of OFC.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Wendy Chung
Title: Genomic Analysis of Congenital Diaphragmatic Hernia and Associated Congenital Anomalies Awardee Organization: Columbia University Health Sciences
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Project Summary/Abstract 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. 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.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Hakon Hakonarson
Title: Genetics at the Intersection of Childhood Cancer and Birth Defects Awardee Organization: The Children's Hospital of Philadelphia
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Evidence of a connection between childhood cancers and birth defects comes from three major sources: clinical observations of syndromes, registry linkages, and case-control studies. These studies demonstrate that children with a variety of birth defects have a significantly increased risk of developing several types of childhood cancers. However, due to the sparsity of cases, few risk factors have been consistently confirmed for specific types of birth defects and childhood cancers, and the etiology of most of these entities remains unexplained. This proposal will leverage the unique resources of The Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia (CHOP) which houses the largest genomic facility/pediatric biobank in the US. We have identified 1,205 pediatric cancer patients that were also diagnosed with a birth defect from the CAG biobank. All have banked DNA samples from peripheral blood that are ready for sequencing together with age, sex and ethnically matched controls. The patients are from diverse backgrounds and the majority of them authorize re-contact. This study will utilize two complementary analytical approaches to disease gene discovery. Patients with parental sequences will be analyzed as trios in a typical winnowing variant prioritization approach. We also propose to sequence matched controls for each of the cases allowing for powerful statistical case control approaches, namely burden tests, to be applied to the dataset. Two strengths of this study design are the large sample sizes for what are rare phenotypes and the combination of birth defects and childhood cancers in all cases which are more likely to be burdened with low frequency variants that confer risk and that more impactful variants are more likely to be discovered. PUBLIC HEALTH RELEVANCE: Birth defects and childhood cancer share biological pathways that are important for cell growth and division. We propose that sequencing pediatric patients suffering both conditions will allow us to discover the underlying genes and in turn advance our understanding of the causes of these devastating diseases.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Daniela Luquetti
Title: Craniofacial Microsomia: Genetic Causes and Pathway Discovery Awardee Organization: Seattle Children's Hospital 
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Craniofacial microsomia (CFM), also termed hemifacial microsomia or oculo-auricular-vertebral spectrum, is the third most common congenital craniofacial condition. CFM has an estimated birth prevalence in the US of 1 in 3,500-5,600, which is similar to conditions such as cystic fibrosis (1 in 3,700) and neurofibromatosis (1 in 4,200). CFM comprises a variable phenotype, and the most common features include malformations of the ear (i.e. microtia) and lower jaw (i.e. mandibular hypoplasia) on one or both sides. The etiology of CFM is largely unknown; however the presence of multiple cases within families, mouse models with CFM malformations and the increased risk of CFM in some ethnicities suggest that genetic variants contribute to its occurrence. Although chromosomal abnormalities have been associated with CFM, only three causative genes have been identified in few cases: HOXA2, FGF3, and MYT1. Our goal in this proposal is to identify coding and non- coding variants that are genetic risk factors to CFM by performing whole-genome sequencing (WGS) of case- parent trios with CFM. We propose to perform whole genome sequencing on DNAs from 105 trios (individuals with CFM and their parents or affected relatives in multi-affected families) to identify candidate genes with rare de novo and inherited variants. Our hypothesis is that CFM is caused by rare new and inherited DNA variation in gene(s) related to the craniofacial development. We will analyze the data on rare de novo coding and non- coding variants. Recognizing reduced penetrance in CFM, our analysis will include analyses for variants in a dominant inheritance with incomplete penetrance model. Our approach incorporates detailed phenotype, clinical characterization, and family history for each individual. We will also integrate the WGS data with our data on gene expression from murine embryonic pharyngeal arch and external ear human embryonic tissue to ascertain tissue specific expression at the relevant time of the development of tissues in CFM. Our statistical power by sampling patients with familial and severe disease who are most likely to have a high genetic loading. CFM represents an ideal condition in which to identify susceptibility variants because it is (1) relatively rare and represents more extreme selection under a liability threshold model, (2) distinctive, (3) stable, and (4) This study will be conducted by an interdisciplinary team with complementary expertise in clinical aspects of CFM, clinical genetics, genomics, and bioinformatics. Successful completion of this proposal will advance knowledge in the genetic architecture of susceptibility to CFM and will provide insight about the biological mechanisms underlying craniofacial development. The phenotypic and genomic data will be fully integrated into the Kids First Data Resource and available to all qualified investigators. The long-term goal of this project is to identify specific genetic risk factors to improve genetic counseling, enable tailored clinical care, and to provide more accurate prognosis. often familial (20-40% of cases). PUBLIC HEALTH RELEVANCE: Craniofacial microsomia (CFM) is the third most prevalent condition that affects craniofacial development; however, the cause of CFM is unknown for most affected individuals. We have established a cohort through previous studies and collected DNA to identify the genetic contributions to CFM, which could facilitate diagnosis, tailored treatment and guide prevention strategies. The results from the proposed study have potential to further research on the etiology of other craniofacial disorders, and the pathogenesis of typical and atypical craniofacial development.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Joshua Schiffman 
Title: Expanded Ewing sarcoma cohort for tumor genomics and association with DNA repair deficiences, clinical presentation, and outcome Awardee Organization: University of Utah
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Expanded Ewing sarcoma cohort for tumor genomics and association with DNA repair deficiencies, clinical presentation, and outcome Ewing sarcoma (ES) is the second most common bone tumor in children and adolescents, but is still relatively rare without much known about genetic risk and only small cohort studies linking tumor genomics to clinical features. Our group was awarded an initial Gabriella Miller Kids First (GMKF) Pediatric Research Program (X01) to study a cohort of germline DNA samples from the Project GENESIS cancer epidemiology study (Genetics of Ewing Sarcoma International Study, COG AEPI10N5), which included whole genome sequencing (WGS) on 329 ES trios (patient-mother-father) plus 123 individual ES patients, with 327 ES patients from the Children’s Oncology Group (COG). The GMKF WGS germline data are now in the process of being returned for analysis. For this expanded study to explore ES tumor genomics, we have assembled a team of leading biologists and clinical scientists in the field of ES along with leaders in the field of genomic sequence analyses and data storage. Utilizing the COG ES Biobank, we will request and submit for sequence analysis the available tumor pairs to the 185 COG ES germline trios plus an additional set of paired COG germline-tumor samples (N=315) to analyze the largest cohort ever assembled of 500 ES germline-tumor pairs for deep sequencing. Using our teams combined expertise, this ES expanded GMKF X01 will test the hypothesis that germline DNA repair deficiencies (as determined by DNA repair gene variants and germline rates of de novo alterations) will contribute to specific tumor genomic features including burden of genomic instability, translocation subtype, transcription profiles, and tumor subclonal heterogeneity (Aim 1). We also will test the hypothesis that these DNA repair deficiencies reflected in the germline will correlate with clinical features of presentation including patient age, sex, tumor site, and tumor stage, as well as test for any correlation between our measured tumor genomic features and clinical presentation (Aim 2). Finally, we will test the hypothesis that the same germline and tumor genomic features will correlate with clinical outcome of the ES patients as reflected in event-free survival and overall survival (Aim 3). Importantly, this study will allow us to determine the prevalence and clinical significance of ES-like tumors that previously were included in ES biological and clinical trials. This expanded GMKF X01 study including ES tumor genomics represents the largest and most comprehensive ES genomic analysis of its kind, and builds upon the successful sequencing of previous ES germline samples through the GMKF X01 program. PUBLIC HEALTH RELEVANCE: Ewing sarcoma (ES) is the second most common bone tumor in children and adolescents, but previous genomic studies have been limited due to this tumor’s overall rarity and difficulty linking to clinical features. Building upon our previous success with sending ES germline samples for whole genome sequencing (WGS) through the Gabriella Miller Kids First (GMKF) Pediatric Research Program (X01), we now will expand our cohort to include tumor samples from within the Children’s Oncology Group (COG) ES Biobank that have been linked to COG clinical trials. We will explore the association between ES tumor genomics and underlying germline DNA repair deficiencies, clinical presentation, and clinical outcome.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Dawn Siegel
Title: Genomic analysis of a cohort with infantile hemangiomas associated with multi-organ structural birth defects Awardee Organization: Medical College of Wisconsin 
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Infantile hemangiomas are the most common benign vascular tumor in infants, affecting 4-5% of children. Thirty percent of segmental infantile hemangiomas on the face and scalp are associated with birth defects of multiple organs. This condition is known as PHACE, an acronym for posterior fossa brain malformations, segmental facial hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal clefting. There is high morbidity associated with PHACE including risk to vision, congenital heart disease often requiring surgery, risk of stroke, deafness and neurodevelopmental delays. The hemangioma is a vascular tumor that requires treatment in infancy to prevent functional complications and disfigurement, but later undergoes involution. Our strategy is to use this highly valuable PHACE cohort to discover critical genes related to structural birth defects which will be a valuable resource to link multiple different projects in the Kids First Program. We hypothesize that PHACE is caused by variants that occur very early during development resulting in birth defects of multiple organs and infantile hemangiomas. Aim 1: Use a custom bioinformatics pipeline to detect candidate variants for PHACE, Aim 2: Contribute the data generated in this project to the Kids First Data Resource and the National Center for Biotechnology Information's (NCBI) and Database of Genotypes and Phenotypes (dbGaP). PUBLIC HEALTH RELEVANCE: Genomic analysis of PHACE will inform treatment and expand knowledge about the causes of birth defects affecting the brain, arteries, heart, eye, midline development and hearing. The knowledge gained in this study will be used to drive strategies for prevention and provide critical targets for treatments for a range of birth defects and infantile hemangiomas.

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Nara Sobreira
Title: Genome-wide Sequencing to Identify the Genes Responsible for Enchondromatoses and Related Malignant Tumors Awardee Organization: Johns Hopkins University
Abstract Text:

Abstract: DESCRIPTION (provided by applicant): Chondrosarcoma is a malignant tumor that originates from cartilaginous cells. It is the third most common primary malignancy of bone after myeloma and osteosarcoma. It accounts for about 20% of bone tumors and is diagnosed in approximately 600 patients each year in the United States. Up to 40% of the chondrosarcomas arise from an enchondroma. Enchondromas are benign, intramedullary cartilaginous tumors of bone. They can be solitary or multiple and are present in >3% of the population. Enchondromatosis refers to a group of diseases characterized by multiple enchondromas including metachondromatosis (MC), Ollier disease (OD), and Maffucci syndrome (MS) among others. All have skeletal abnormalities with or without associated vascular anomalies that can cause severe limb deformities during early childhood. The risk for chondrosarcoma in OD is up to 45.8% and in MS up to 57.1%. Currently, the only treatment for patients with these disorders is surgical; there is no effective pharmacologic therapy. We identified heterozygous germline loss of function variants in PTPN11 (encoding a non-receptor protein tyrosine phosphatase SHP2) causing MC (Sobreira at al., 2010). In preliminary studies, we also identified the PTPN11 R138X variant in in a retiform hemangioendothelioma of a patient with MS and the germline PTPN11 L560F variant in a patient with OD. PTPN11 encodes SHP2, a cytosolic protein tyrosine phosphatase involved in an early step in RAS/MAPK signaling downstream of several receptor tyrosine kinases including EGFR and FGFR. Pansuriya et al. (2011) and Amary et al. (2011) identified heterozygous somatic variants of IDH1 (R132H, R132C, R132S) and IDH2 (R172S) in the tumors (enchondromas, chondrosarcoma, and hemangiomas) of a fraction of the patients with MS and OD. Neither variant was identified in the germline DNA of the affected individuals. On basis of these results, we hypothesize that OD and MS are tumor predisposition syndromes caused by germline variants. Moreover, these variants likely down-regulate the RAS/MAPK pathway or are in genes that interact with IDH1 or 2. Subsequent hits in the same or different genes such as IDH1 and IDH2 or other as yet identified genes are involved in the formation of enchondromas and chondrosarcomas. PUBLIC HEALTH RELEVANCE: : Ollier disease and Maffucci syndrome are characterized by multiple enchondromas that can cause multiple swellings on the extremity, deformity around the joints, Madelung deformity, angular deformity such as genu valgus, gene varum, cubitus valgus, coxa vara and coxa valga, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain and loss of function, pathological fractures, facial asymmetry and cranial nerve palsies and the risk of developing a chondrosarcoma in patients with Ollier disease is up to 45.8% and up to 57.1% in patients with Maffucci syndrome. In addition, gliomas, acute myeloid leukemia, and juvenile granulosa cell tumors have been found in patients with OD and pancreatic and hepatic adenocarcinoma, mesenchymal ovarian tumors, brain tumors such as glioma and astrocytoma, and various kinds of sarcomas are observed in patients with MS (Verdegaal et al., 2011). The molecular basis of this two disorders is not completely understood and currently, there is no effective drug therapy for these disorders.

Back to the Funded Research.

Up to Top


FY16 X01 Projects for the Gabriella Miller Kids First Program

Project Number: N/A Contact PI / Project Leader: Wendy K. Chung 
Title: Genomic Analysis of Congenital Diaphragmatic Hernia and Associated Congenital Anomalies 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 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.

 

 

Anticipated number trios (parents and proband) to be sequenced: 942 + 15 (long read pilot)

Back to the Funded Research.

Up to Top

Project Number: N/A 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 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 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.

 

Anticipated number trios (parents and proband) to be sequenced: 831 + 15 (long read pilot)

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: John M. Maris 
Title: Genetic basis of neuroblastoma initiation and progression Awardee Organization: Children's Hospital of Philadelphia
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced:  2154

Back to the Funded Research

Up to Top

Project Number: N/A Contact PI / Project Leader: Charles G. Mullighan
Title: Genomic analysis of familial leukemia Awardee Organization: St. Jude Children's Research Hospital
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 483

 

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Sharon E. Plon
Title: Identifying novel cancer susceptibility mutations from unselected childhood cancer patient and parent trios Awardee Organization: Baylor College of Medicine
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 371

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Jonathan Rios
Title: Genomics of Orthopaedic Disease Program Awardee Organization: UT Southwestern Medical Center
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 300

Back to the Funded Research.

Up to Top

Project Number: N/A 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 Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 1275

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Jun Shen
Title: Hear-n-Seq: Sequencing Kids First for Hearing Awardee Organization: Brigham and Women's Hospital
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 437

Back to the Funded Research.

Up to Top


FY15 X01 Projects for the Gabriella Miller Kids First Program

Project Number: N/A 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.

 

Anticipated number trios (parents and proband) to be sequenced: 200
Sequence and clinical data released in dbGap:  accession number-phs00110

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Elizabeth C. Engle 
Title: BCH Structural Birth Defects Collaboration: Syndromic cranial dysinnervation disorders Awardee Organization: Children’s Hospital Corporation
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 300
Estimated public release of sequence and clinical data: September 2017

Back to the Funded Research.

Up to Top

Project Number: N/A 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.

 

Anticipated number trios (parents and proband) to be sequenced: 430
Estimated public release of sequence and clinical data: September 2017

Back to the Funded Research.

Up to Top

Project Number: N/A 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.

 

Anticipated number patients to be sequenced: 198 germline samples and 452 tumor samples (198 pre- and post- treatment tumor samples & 56 relapse/metastasis tumor samples)
Estimated public release of sequence and clinical data: Late 2017

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Joshua D. Schiffman 
Title: Genetic Contribution to Ewing Sarcoma in 330 parent-Offspring Trios Awardee Organization: University of Utah
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 370
Estimated public release of sequence and clinical data: November 2017

Back to the Funded Research.

Up to Top

Project Number: N/A 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
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 300
Estimated public release of sequence and clinical data: February 2017

Back to the Funded Research.

Up to Top

Project Number: N/A Contact PI / Project Leader: Eric J. Vilain  
Title: Genetic Basis of Disorders/Differences of Sex Development (DSD) Awardee Organization: University of California Los Angeles
Abstract Text:

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.

 

Anticipated number trios (parents and proband) to be sequenced: 100
Estimated public release of sequence and clinical data: February 2018

Back to the Funded Research.

Up to Top

This page last reviewed on October 16, 2017