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Project Number: 1 X01 HL145692-01  Contact PI / Project Leader: Chung, Wendy K (Contact); Shen, Yufeng
Title: Genomic Analysis of Esophageal Atresia and Tracheoesophageal Fistulas and Associated Congenital Anomalies Awardee Organization: Columbia University Health Sciences

Abstract:

DESCRIPTION (provided by applicant): 

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a rare and complex aerodigestive congenital anomaly with an estimated incidence of 1 in 2500 to 1 in 4000 live births. There is a 45% incidence of associated congenital malformations, most commonly digestive, cardiovascular, urogenital, and musculoskeletal, often part of a syndrome or complex association, with VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities) being most frequently recognized. Advanced surgical techniques and pre and post-operative care have improved the prognosis and survival of EA/TEF patients over the past decades. However, with improved survival, many of the long-term morbidities of EA/TEF have been exposed. It is likely that the outcome in EA/TEF patients is influenced by multiple genetic and clinical factors; however, determining which factors are critical has been limited by the lack of data, particularly genomic data. 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. 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 EA/TEF and define new genes and conditions associated with EA/TEF by performing whole genome sequencing on 100 parent child trios in a clinically well characterized cohort to identify rare de novo mutations and inherited variants. We believe this information will improve genetic diagnostic methods and provide more accurate clinical prognostic information to guide clinic decisions and improve outcomes. PUBLIC HEALTH RELEVANCE: Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a rare and complex aerodigestive congenital anomaly with an estimated incidence of 1 in 2500 to 1 in 4000 live births. We propose to elucidate the underlying genomic architecture of EA/TEF by performing whole genome sequencing to characterize new clinical syndromes associated with EA/TEF to provide more accurate clinical prognostic information.

 

Project Number: 1 X01 HL145691-01   Contact PI / Project Leader:  Seidman, Christine E
Title: Germline Mutations in CHD Awardee Organization: Harvard Medical School

Abstract:

DESCRIPTION (provided by applicant): 

Congenital heart disease (CHD) is the most common birth defect and is often accompanied by another congenital anomaly (CHD±CA). The Pediatric Cardiovascular Genetics Consortium (PCGC) is committed to defining the molecular mechanisms for CHD±CA. We have recruited over 29,000 participants including over 6000 CHD probands and parents (CHD trios) with extensive clinical data. Whole exome sequence (WES) analyses in ~3300 CHD trios by the PCGC has defined likely genetic causes in ~40% probands. As part of the Gabriella Miller Kids First Pediatric Research Program, we propose WGS to enable the discovery of variants and mechanisms that contribute to unexplained CHD in ~60% of probands studied by the PCGC. To accomplish these goals we will capitalize on new insights into CHD genes, identified by WES, that indicate aberrant transcriptional regulation during development is a major cause of CHD. In this application we request WGS on 550 CHD trios so that by leveraging existing genomic datasets we will empower robust analyses of variants that alter noncoding regulatory elements of cardiac development genes in WES-negative trios. Nested within this trio group are 100 CHD trios comprised of a proband with one damaging variant in a recessive CHD gene. In addition to genome-wide studies, focused analyses in this trio subgroup will search for noncoding variants that impact the “normal” allele. The remaining 450 CHD trios include probands with tetralogy of Fallot (ToF), the most common form of cyanotic heart disease. We will harness WGS in ToF trios to inform variants within particular genome regions that are susceptible to recurrent copy number and structural variants - regions that are poorly interrogated by WES. While mutation in these several variant-susceptible genes and loci are often found in ToF patients, these are remarkably absent in many ToF probands studied by WES and CNV analyses. Finally, we request high-depth WGS of 200 discarded CHD tissues obtained during surgical repair, to explore novel genetic mechanisms in CHD, including somatic mosaicism, mitochondrial variants, and to provide initial evidence of prenatal infections that may contribute to CHD. In all of these studies 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. We request: 1. WGS (90X coverage) on 200 CHD tissues. 2. WGS on 100 CHD trios comprised of a proband with a damaging variant in a recessive CHD gene. 3. WGS on 450 TOF trios. PUBLIC HEALTH RELEVANCE: Using whole genome sequencing, we aim to discover the genetic mechanisms for congenital heart disease, the most common human birth defect. We will identify sequence variants that alter regulatory elements involved in developmental transcription and consider the consequences of these on discarded heart tissues obtained during surgical repair of heart malformations. Through focused analyses of tetralogy of Fallot, we hope to better understand the processes that promote this complex and prevalent heart malformation.

 

Project Number: 1 X01 HL145698-01 Contact PI / Project Leader: Gharavi, Ali G
Title: Genetics of Structural Defects of the Kidney and Urinary Tract  Awardee Organization: Columbia University Health Sciences

Abstract:

DESCRIPTION (provided by applicant): 

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) account for up to 50% of pediatric and 7% of adult end-stage kidney failure worldwide. The goal of this project is to apply genetic approaches to resolve the biological basis and clinical manifestations of CAKUT using three well-characterized cohorts with deep phenotypes and extensive longitudinal data (the NIDDK sponsored CKiD and RIVUR studies, and the Columbia cohort). Here, we hypothesize that CAKUT is genetically heterogeneous, and caused by rare mutations with large effect on a background of polygenes with small effects that can be discovered by analysis of well phenotyped cohorts compared to genetically matched cohorts with WGS data available. We now propose to extend our prior studies by whole genome sequencing (GWS) in patients with CAKUT from 3 well-phenotyped cohorts. We expect that the proposed studies will provide new insight into urogenital development, clarify the clinical overlap with other syndromes and provide novel tools that can replace the current morphology-based diagnostic approaches. We will first perform annotation based on a standard ACMG guidelines to identify pathogenic CNVs and single nucleotide variants diagnostic for known genetic disorders. In aim 2, we will perform genome-wide analysis of common and rare variant burden combining a case-control and trio design to detect new genes for CAKUT. We will next replicate top signals in additional CAKUT cohorts available in our laboratory. Finally, we will per phenotype- genotype correlations with longitudinal clinical data such a kidney function, proteinuria or neurodevelopmental outcomes to gain insight into clinical impact of causal variants. PUBLIC HEALTH RELEVANCE: Congenital defects of the kidney and urinary tract are a common cause of kidney failure in children and adults and elucidation of the genetics of these disorders will provide new opportunities for diagnosis, risk stratification and prevention of complications.
Sequence and clinical data released in dbGap:Accession Number:phs002162

 

Project Number: 1 X01 HL145697-01 Contact PI / Project Leader: Krantz, Ian
Title: Genomic Diagnostics in Cornelia de Lange Syndrome, Related Diagnoses and Structural Birth Defects Awardee Organization: Children's Hospital Of Philadelphia

Abstract:

DESCRIPTION (provided by applicant): 

Disorders of human morphogenesis are a major cause of human suffering for the affected individuals and their families. Congenital anomalies are identified in approximately 3% of term births, 10% of stillbirths, and in as many as 50% of first trimester spontaneous abortuses. While most, if not all, human structural birth defects have a significant genetic component, identification of genetic perturbations in isolated structural birth defects has been complicated by the complex nature of their underlying etiologies, likely involving disruption of regulatory elements that can act in a temporal and tissue specific manner, multi-gene, epigenetic and gene-environment interactions. Our approach to tease out genetic contributions to birth defects has been to identify the underlying causes of syndromic birth defects which are often Mendelian in nature and therefore lend themselves more readily to genetic causal identification. Once identified, these genetic causes of syndromic forms of birth defects can be leveraged to understand the genetic contributions to isolated birth defects seen in constellation in these syndromes. We propose to use Cornelia de Lange Syndrome (CdLS), a dominant multisystem developmental disorder consisting of a constellation of structural birth defects involving most body systems and significant growth and cognitive impairment as a prime example of this approach. We and others have shown that alterations in the cohesin and associated pathways are causative of CdLS and related diagnoses when disrupted and have more broadly been termed “cohesinopathies” or “disorders of transcriptional regulation (DTRs)”. In this proposal we outline an initial plan to perform genome sequence (subsequently RNA sequencing will be considered) on a unique cohort of 501 probands and family members with clinically confirmed CdLS or a related diagnosis in whom molecular analysis by targeted gene sequencing, next generation sequencing (NGS) panels or exome sequencing have been negative but are strongly suspected of having an underlying genetic alteration to explain their clinical features. This work will lead to the identification of genes critical in human embryonic development, provide novel insights into transcriptional regulation and help to identify genetic causes and candidate genes for isolated birth defects seen in constellation in this group of diagnoses. Most critical developmental genes are also cancer genes and the genes known to cause CdLS are no exception. CdLS is not a cancer predisposition syndrome so understanding the mutational mechanisms in these genes that lead to structural birth defects when present in the germ line and result in cancer when mutated somatically is a fundamental aspect of this research. PUBLIC HEALTH RELEVANCE: The proposed research Program is relevant to public health as we are addressing a major gap in our understanding of the genetic basis of syndromic and non-syndromic structural birth defects (with a focus on Cornelia de Lange syndrome and related diagnoses and birth defects), a major cause of human suffering for the affected individuals and their families. The proposed research Program is highly relevant to the NIH mission of improving health outcomes as we expect that discoveries of the basic mechanisms of structural birth defects will lead to improved diagnostics, counseling, management and therapeutics for affected individuals and their families.

 

Project Number: 1 X01 HL145690-01 Contact PI / Project Leader: Seidman, Jonathan G
Title: The Genetics of Microtia in Hispanic Populations Awardee Organization: Harvard Medical School

Abstract:

DESCRIPTION (provided by applicant): 

Microtia is a rare congenital deformity of the external ear, the pinna. The severity of microtia is variable and ranges from subtle deformities in the pinna to absence of the external ear. Microtia is often associated with closure of the external auditory ear canal causing significant hearing loss. Microtia can be an isolated, unilateral or bilateral malformation, or occur solely with ear canal deformities, or with additional craniofacial or syndromic manifestations. Our study of identical twins with microtia demonstrated a significant genetic contribution. The molecular pathogenesis for most microtia remains unknown. We propose to leverage our clinical acumen in diagnosis and treatment of microtia (R.E.), our relationship to the microtia community (M.T.) and our collected DNA samples from microtia patients to identify genetic variant(s) that contribute to this congenital malformation. Microtia prevalence is much higher among Native Americans and some Latin Americans (17 per 10000 Ecuadorian births) than among individuals of European-descent (0.6 -1.6 per 10,000 births). To capitalize on this epidemiologic data, we have recruited microtia cohorts from Latin America and the U.S, including clinical data and DNA samples. We propose whole genome sequence of existing samples from isolated cases, trios (proband and parents) and one large family we propose comprehensive genetic analyses to interrogate coding and non-coding sequence variants associated with microtia. We hypothesize that genetic variants that cause microtia and other less pathogenic conditions, which have relatively small impact on reproductive fitness, are likely to be tolerated and inherited, but cause malformations in only a fraction of variant carriers (i.e. reduced penetrance). We suggest that we have power to detect a variant that increases the relative risk of microtia by >2.5 (i.e. a penetrance of ~3%). We suggest that microtia likely reflects variants with low penetrance that impact genes that participate in the molecular pathways of ear development. Such variants may also contribute to other hearing and craniofacial malformations. We expect to harness the insights and reagents developed here to elucidate factors that impact the penetrance of variants. Because of the prevalence of microtia in Latin America there are microtia support groups in Mexico, Colombia, and Ecuador. We have formed alliances, through our collaborator Melissa Tumblin (Ear Community), with these microtia support groups. We anticipate that any associations detected in the preliminary whole genome sequence (WGS) cohort will be confirmed in a second cohort of microtia patients. We request that the Gabrielle-Miller Kids First program support WGS of 821 microtia subjects and their parents as follows: a) 200 microtia probands; b) 200 trios (proband and both parents) and c) 21 members of family 3Sz. PUBLIC HEALTH RELEVANCE: We request whole genome sequence of 821 Hispanic subjects who have at least one family member with microtia, or abnormal outer ear formation. There are 200 microtia probands without parents, and 200 microtia probands with parents (trios, n=400) and 21 from a large family with 6 cases of microtia. We expect that analysis of the WGS will identify a gene variant(s) that increases the risk of microtia in some Latin American populations by ~25 fold and will provide new insights into the development of the outer ear.
Sequence and clinical data released in dbGap:Accession Number:phs002172

 

Project Number: 1 X01 HL145702-01 Contact PI / Project Leader: Chambers, Christina
Title: Discovery of Genetic Basis of Fetal Alcohol Spectrum Disorders Awardee Organization: University Of California, San Diego

Abstract:

DESCRIPTION (provided by applicant): 

Fetal Alcohol Spectrum Disorder (FASD) is the most common birth defect worldwide, and is estimated to occur in at least 1-5% of all children in the U.S. However, not all children with prenatal exposure are similarly affected, even among those born to heavy, chronic alcohol-consuming pregnant women. Recent research has focused on the susceptibility or protective factors that seem to influence the risk for FASD. However, very little is known about the genetic risk or protective factors that may interact with prenatal alcohol exposure leading to this variable risk. In this study, we will use whole genome sequencing of well-characterized mother-child pairs, including mothers with or without prenatal alcohol exposure and their children with or without FASD, to test the hypothesis that genomic alterations in either the mother or her fetus or both play a role in susceptibility to the effects of alcohol. This information will be of critical value in better understanding the pathogenetic mechanisms underlying FASD. In addition, the identification of maternal or fetal genetic susceptibility factors for FASD may inform future intervention strategies for this common congenital disorder. PUBLIC HEALTH RELEVANCE: Fetal Alcohol Spectrum Disorder (FASD) is estimated to occur in at least 1-5% of all children in the U.S. and is a major public health issue. However, in addition to alcohol, other susceptibility factors, such as maternal or fetal genetic variation, must play a role as not all children prenatally exposed to alcohol are similarly affected. The proposed study will examine the role of genetic susceptibility for FASD; this work will help to inform more effective intervention efforts for this common congenital disorder

 

Project Number: 1 X01 HL145686-01   Contact PI / Project Leader: Lupo, Philip J (Contact); Rabin, Karen R; Sherman, Stephanie L.; Yang, Jun J
Title: Genomic Analysis of Congenital Heart Defects and Acute Lymphoblastic Leukemia in Children with Down Syndrome Awardee Organization: Baylor College Of Medicine

Abstract:

DESCRIPTION (provided by applicant): 

Down syndrome (DS), which occurs due to trisomy 21, is one of the strongest risk factors for both congenital disease (CHD) and acute leukemia. For instance, children with DS have a 2000-­fold increased risk of atrioventricular septal defects (AVSD) and a 20-­fold increased risk of acute lymphoblastic leukemia (ALL). An important and innovative aspect of the Kids First program is understanding the overlap between structural birth defects and childhood cancer. Notably, the background of DS predisposes children to both phenotypes, however, the genomic architecture of risk remains largely undiscovered. Therefore, we propose that our assembled cohort of children with: 1) DS alone (n=607) 2) DS with AVSD (DS-­AVSD, n=623) 3) DS with other CHD (DS-­oCHD, n=594) and 4) DS with ALL (DS-­ALL, 370) will advance our understanding of the developmental pathways that may lead to both structural birth defects and childhood cancer. The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS. Our central hypothesis is that risk-­associated genetic variants in the background of DS lead to a higher penetrance of AVSD and ALL. Our secondary hypothesis is that rare variants explain a significant proportion of the increased risk of AVSD and ALL in children with DS. Our hypotheses are supported by our previous work indicating: 1) previously identified susceptibility loci in ALL genes (e.g., IKZF1) have stronger effects in children with DS-­ALL compared to non-­DS-­ALL 2) common genetic variants and copy number variants do not explain the increased risk of AVSD among those with DS and 3) there is an increased burden of rare variants among children with DS-­AVSD compared to those with DS alone. Therefore, the aims of our study are: 1) compare whole-­genome sequencing (WGS) data between children with documented DS-­AVSD and children with DS who have structurally normal hearts to identify genetic variants that perturb heart development and 2) compare WGS data between children with documented DS-­ALL and children (from Aim 1) with DS who do not have a known history of ALL. For the subset of DS-­ALL cases with a paired tumor sample, we will examine associations between germline mutations and somatic genomic features. This study will address the fundamental question of why children with DS have an elevated risk of AVSD and ALL. Insights into the genes that drive DS-­AVSD and DS-­ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these children. Additionally, our findings may inform targeted therapies or interventions for children without DS who are at risk for structural birth defects and cancer.  PUBLIC HEALTH RELEVANCE: PROJECT   Children with Down syndrome (DS), which occurs due to trisomy 21, have a 2000-­fold increased risk of atrioventricular septal defects (AVSD) and a 20-­fold increased risk of acute lymphoblastic leukemia (ALL), but it is not understood which genetic features of trisomy 21 are responsible for the increased risk. The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS, which builds upon our previous work suggesting having an extra copy of chromosome 21 may “move” the susceptibility threshold for disease in these children. Insights into the genes that drive DS-­AVSD and DS-­ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these and other children who may develop AVSD or ALL.

 

Project Number: 1 X01 HL145695-01  Contact PI / Project Leader: Drolet, Beth A
Title: Analyzing the Genetic Spectrum of Vascular Anomalies, Overgrowth and Structural Birth Defects Awardee Organization: Medical College Of Wisconsin

Abstract:

DESCRIPTION (provided by applicant): 

Vascular anomalies include a heterogeneous group of tumors and malformations characterized by the presence of abnormal vascular structures. Vascular anomalies most often occur in the skin and soft tissue; however, they can occur within any organ and present with a wide range of symptoms and complications, depending on type and location of the lesion. These disorders are remarkably variable ranging from simple staining of the skin with mild soft tissue overgrowth to debilitating tissue overgrowth and severe structural birth defects. We assembled a large vascular anomalies cohort recruited from a 20-institution network to discover genes related to vascular anomalies and structural birth defects. Using targeted next-generation sequencing, we and others, have detected postzygotic mosaic variants in affected tissue from several vascular anomalies. The causative variants almost entirely overlap with those variants observed in cancer. The preliminary data generated from this cohort reinforces the approach set forth by the Gabriella Miller Kids First Program by demonstrating a direct connection between cancer and structural birth defects. We hypothesize that vascular anomalies are caused by postzygotic somatic mutations and that the phenotype is further influenced by the mutational burden, the tissue distribution of mutation, and germline alterations, which establish a necessary context in which postzygotic alterations act. Improved understanding of the complex genetic landscape of vascular anomalies will be critical for accurate diagnosis, the development of care guidelines, consideration of therapeutic options, and planning of future clinical trials. Aim 1: Identify genomic alterations in vascular anomalies, Aim 2: Contribute the data generated in this project to the Kids First Data Resource and the National Center for Biotechnology Information’s (NCBI) Database of Genotypes and Phenotypes (dbGaP). PUBLIC HEALTH RELEVANCE: Genomic analysis of vascular anomalies will inform treatment and expand knowledge about the causes of birth defects affecting blood vessels, brain, eye, and bones. The knowledge gained in this study will be used to drive strategies for prevention and provide critical targets for treatments for vascular anomalies and related birth defects.

 

Project Number: 1 X01 HL145696-01  Contact PI / Project Leader: Meshinchi, Soheil  
Title: Germline and Somatic Variants in Myeloid Malignancies in Children Awardee Organization: Fred Hutchinson Cancer Research Center

Abstract:

DESCRIPTION (provided by applicant): 

Advances in genomic sequencing has allowed identification of somatic variants as potential therapeutic targets. Although myeloid disorders in children may show morphologic similarities to that seen in adults, TARGET AML initiative (Meshinchi, PI) clearly demonstrated that somatic genomic and transcriptome variants are highly distinct in children and young adults, and in fact there are variants that are uniquely restricted to younger children. TARGET AML initiative, although modest in number, helped identify numerous somatic alterations with high therapeutic potential in younger AML patients. In addition to identification of somatic variants, analysis of the germline data provided a glimpse into the constitutional make-up of patients with AML. The identification of numerous “function altering” variants may provide an insight into possible interactions between the host and the disease, where these germline variants might alter AML risk (predisposition), response to therapy (altering target expression, drug metabolism), susceptibilities to short and long term complications (including infectious and cardiac complications) or modify risk of secondary malignancies. Armed with data from initial sequencing efforts in AML, we are poised to take full advantage of the available sequencing technology to conduct the most comprehensive genome and transcriptome interrogation of myeloid disorders in children in specimens we have amassed over the last decade. To this end, we have put in place unparalleled specimen resources from children with de novo AML, Down Syndrome AML (DS-AML), and acute promyelocytic AML (APL) treated on COG trials. In addition, thru collaboration with Dr. Resar and Kucine, we will be able to conduct the first broad sequencing study in the rare entity of myeloproliferative neoplasms of childhood (MPN-c). Identification of the somatic variants will provide valuable data on the potential genes and pathways that can be targeted for therapeutic gains. In addition, interrogation of the host’s constitutional genome may yield valuable information about potential germline variants that, in combination with the somatic data, might provide a more informed approach to patient care. For those patients with predisposition mutations, chemotherapy alone might not be adequate for cure and stem cell transplantation might be required. Also, those who might be at high risk of adverse secondary events (cardiac complications, secondary malignancies, etc.) can be identified early and their therapy tailored to minimize anticipated complications. Thus, we propose that the optimum outcome can only be obtained thru comprehensive interrogation of the somatic and germline genome to fully annotate the genomic makeup of the leukemia and its host. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Clinical outcome in children with myeloid disorders have remained poor in part due to lack of deep understanding of the genomic makeup of the disease as well as the host. Comprehensive studies of the host and disease may enable more informed therapies in order to optimize targeting the leukemia while minimizing short and long term toxicities, leading to improved survival with minimal morbidities.

 

Project Number: 1 X01 HL145700-01  Contact PI / Project Leader: Lau, Ching Ching (Contact); Poynter, Jenny N.
Title: Genetic Predisposition to Intracranial Germ Cell Tumors Awardee Organization: The Jackson Laboratory

Abstract:

DESCRIPTION (provided by applicant): 

Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors that most commonly occur in the gonads but also develop in other locations. Intracranial GCTs (IGCTs) account for approximately 3% of brain tumors in children in the U.S. but are far more prevalent in Japan and East Asian countries, where they account for up to 11% of brain neoplasms. These observations suggest that there is genetic predisposition to IGCT. Currently little is known about the etiology of IGCTs. Their incidence peaks in the second decade of life with rates that vary widely by geography and are higher in males than in females. Recent reports support familial aggregation of IGCT. Data from the PIs of this project support the hypothesis that genetic variants contribute to IGCT predisposition, as rare variants in the gene JMJD1C were identified among a Japanese patient population in strong association with IGCT. JMJD1C is a plausible susceptibility gene for IGCT given its role in sex steroid hormone regulation and maintenance of male germ cells in mice. Additionally, it has been hypothesized that intracranial and other GCTs both arise from primordial germ cells that migrated abnormally during development. Indeed, using case parent trios recruited for a Children’s Oncology Group (COG), the PIs of this project found that common genetic variants associated with adult testicular GCT are also associated with both intracranial and systemic GCT, suggesting that there may be common genetic risk factors for all GCT types. Identification of additional genetic variants for IGCT risk will require a larger study using whole-genome sequencing (WGS) data. To test the hypothesis that there are genetic variants that increase susceptibility to pediatric IGCT development, this project will carry out three Aims that focus on a cohort of more than 400 IGCT cases from the U.S., Japan, and Thailand. Aim 1 will validate the importance of JMJD1C as a susceptibility locus for IGCT in Japanese and non-Japanese populations by identifying additional rare and novel variants that are over-represented in IGCT, which are expected to occur at a much higher frequency in Japanese IGCT cases. Aim 2 will identify novel susceptibility variants for IGCT that are enriched in the Japanese population by applying a previously developed filtering approach. Aim 3 will identify novel variants associated with IGCT using aggregate burden tests, focusing on genes and established regulatory regions. This analysis will improve the power to identify novel variants associated with IGCT in the entire cohort of samples and is anticipated to enable identification of familial predisposition for IGCT in both known and unrecognized cancer susceptibility genes. The availability of IGCT whole-genome sequencing data through the Gabriella Miller Kids First Data Resource Center will offer the cancer research community an opportunity to investigate the genetic basis of IGCT and promote the clinical risk assessment and treatment of this cancer. Additionally, the identification of associated genetic variants is anticipated to inform the understanding of other forms of pediatric cancers. PUBLIC HEALTH RELEVANCE: / RELEVANCE TO PUBLIC HEALTH Pediatric intracranial germ cell tumors (IGCTs) account for approximately 3% of brain tumors in children in the U.S. but are far more prevalent in Japan and East Asian countries, where they account for up to 11% of brain neoplasms. To understand the genetic risks of developing this cancer type in childhood, we have gathered hundreds of cases from the U.S., Japan, and Thailand so that their genomes can be fully sequenced through the Gabriella Miller Kids First Pediatric Research Program and be made publicly available as part of the Kids First Data Resource. We will computationally analyze this sequencing data to identify those genetic variants that are associated with IGCT and determine which gene functions are perturbed by these variants to increase susceptibility to this disease.

 

Project Number: 1 X01 HL140546-01A1 Contact PI / Project Leader: Jelin, Angie Child
Title:  Single gene pathogenic variants associated with BEEC (Bladder extrophy, Epispadias, Complex) Awardee Organization: Johns Hopkins University

Abstract:

DESCRIPTION (provided by applicant): 

This X01 application is submitted by Angie C. Jelin, MD, Assistant Professor of Gynecology and Obstetrics/Genetics at the Johns Hopkins School of Medicine. Dr. Jelin’s long term goal is to become an independent investigator in fetal urinary tract anomalies. Towards this goal, she proposes whole genome sequencing (WGS of Bladder Exstrophy Epispadias Complex (BEEC). Urogenital anomalies account for 20-30% of prenatally detected structural defects. BEEC describes a subset of anomalies with a spectrum of developmental defects ranging from a mild form of epispadias, to classic bladder exstrophy, to omphalocele, exstrophy, imperforate anus, spinal anomalies (OEIS) complex. Patients with BEEC suffer substantial morbidity and mortality due to impaired genito-urinary dysfunction. The etiology of BEEC is largely unknown. Elucidating the underlying genetic component is critical to gaining a better understanding of the developmental signaling pathways and is likely the first step to developing targeted therapy. Variants in genes identified in other urogenital anomalies appear to be responsible for some cases of BEEC including IS, WNT3, WNT9b, PLAG1 and p63. We propose to take advantage of our extensive analytical experience in the Baylor Hopkins Center for Mendelian Genomics and perform WGS on parent-proband trios for whom the proband has BEEC. One study utilizing whole exome sequencing (WES), identified candidate genes (SLC20A1 and CELSR3) in 2 out of 8 affected patients, providing reassurance that our proposed strategy will be successful. Following WGS, we will explore the pathogenicity of genetic variants by employing a knockout mouse model using CRISPR/Cas9 technology via collaboration with the Jackson Laboratory. Final validation will include mouse phenotyping by dynamic contrast-enhanced MRI under the expertise of, Cory Brayton, mouse pathologist. Aim 1. To identify the genetic basis of BEEC through Whole Genome Sequencing (WGS) Aim 2a. To create the founder (F0) homozygous knockout mouse using CRISPR/Cas9. Aim 2b. To define the murine model phenotype using dynamic contrast enhanced MRI. PUBLIC HEALTH RELEVANCE: Patients with Bladder Exstrophy Epispadias Complex suffer substantial morbidity and mortality due to impaired genito-urinary dysfunction. The etiology of BEEC is largely unknown. Elucidating the underlying genetic component is critical to gaining a better understanding of the developmental signaling pathways and is likely the first step to developing targeted therapy.

 

This page last reviewed on November 14, 2023

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