FY20 X01 Projects for the Gabriella Miller Kids First Program

Project Number: HL155060-01 Contact PI / Project Leader: Chung, Wendy K 
Title: Genomic Analysis of Congenital Diaphragmatic Hernia Awardee Organization: Columbia University Health Sciences
 
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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 and/or primary abnormalities in lung development. 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. Many birth defects can result from rare de novo mutations and inherited rare variants. We propose to identify genes that increase the risk of CDH by performing whole genome sequencing on parent child trios and singletons 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.

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Project Number: DE030062-01 Contact PI / Project Leader: Marazita, Mary 
Title: Kids First: Genomics of Orofacial Cleft Birth Defects in Families from Puerto Rico, Central and South America Awardee Organization: University of Pittsburgh
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Abstract: DESCRIPTION (provided by applicant):): Nonsyndromic orofacial clefts (OFCs) of the lip (CL), palate (CP), or both (CLP) occur in about 1/700 live births worldwide, and thus comprise a significant proportion of human structural birth defects. OFCs require surgical, nutritional, dental, speech, medical, and behavioral interventions, and thus impose substantial public health, economic, and personal burdens. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). The etiology of OFCs is complex, and includes a major genetic component, with approximately 30 associated loci identified to date. However, critical gaps in our understanding persist, as previously discovered variants explain only a portion of the heritable risk for OFCs. Notably there are distinct ethnic differences in the epidemiological patterns of OFCs, which may reflect underlying genetic differences, such as different primary risk genes, or different frequencies of risk alleles. A major goal of our overall research strategy is to apply genomic approaches in families from multiple populations world-wide. Latin American families are at high risk for OFC birth defects and the goal of the current new project is to apply whole genome sequencing (WGS) to better understand the genetic architecture of OFCs in Latin America. Prior GMKF WGS of 276 Colombian trios from our study identified a novel locus on chromosome 21, illustrating the utility of analyses in Latin Americans which are one of the population groups at highest risk for OFC. The goal of this new study is to apply WGS in additional Latin American trios (available are 844 trios not overlapping previous WGS efforts), adding trios from Puerto Rico, Guatemala, Argentina and other sites to continue to seek Latin American specific OFC risk loci in these new trios, and for meta-analyses with the other existing GMKF OFC trios (including the prior 276 Colombian trios). PUBLIC HEALTH RELEVANCE: Latin American families are at high risk for orofacial cleft birth defects such as cleft lip and cleft palate. The goal of this project is to better understand the genetic architecture of these birth defects by performing whole genome sequencing in Latin American families.

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Project Number: HL155057-01 Contact PI / Project Leader: Weaver, Kathryn 
Title: Genetic diagnoses in a cohort of individuals with valvar pulmonary stenosis Awardee Organization: Cincinnati Children's Hospital Medical Center

 
Abstract Text:

Abstract: DESCRIPTION (provided by applicant):Congenital heart disease (CHD) affects 1% of live births and has both monogenic and multifactorial causes. There are multiple studies investigating genetic contribution to specific cardiac defects, e.g. left ventricular outflow tract obstruction and conotruncal defects. However, the prevalence of genetic diagnoses among individuals with vPS, which accounts for 8-12% of CHD, is unknown. Further, complex etiologies for vPS remain largely unexplored. This is despite studies of familial CHD which indicate that right ventricular outflow tract obstructive defects such as vPS are one of the more heritable forms of CHD. A diagnosis of vPS represents a significant healthcare burden: One quarter of individuals with vPS require invasive treatment with balloon valvuloplasty and/or open heart surgical repair, and a subset of these will require repeat intervention for recurrent valve stenosis, or due to interval development of valve insufficiency/regurgitation. Several genetic syndromes are associated with vPS, most commonly Noonan syndrome, but etiology is unknown in the majority of cases. Individuals with vPS due to Noonan syndrome are more likely to require intervention and re-intervention; however, many studies about vPS outcomes predated currently available genetic sequencing technology. We recently performed a retrospective analysis showing that 6% of 204 children (aged 0-4 years) with vPS have a Noonan syndrome spectrum diagnosis and 10% have a genetic diagnosis; however, only 18% of the cohort had a genetic evaluation. We subsequently analyzed a cohort of 105 probands with vPS in the Pediatric Cardiac Consortium (PCGC) cohort who had trio exome and phenotypic data available. Overall, 20 (19%) had a likely genetic etiology identified with exome sequencing, twice the incidence of genetic diagnosis in our cohort of 204, the majority of whom had not had a genetics evaluation. This suggests that genetic contribution to vPS may be under recognized. We propose whole genome sequencing (WGS) on a multi-institutional cohort of individuals with vPS. This includes 109 trios, 101 parent/proband duos, and 364 singletons, for a total of 574 probands, from two major children’s hospitals and the PCGC. Analysis of WGS data will accomplish the following three specific aims: 1) determine the prevalence of known genetic diagnoses among a cohort of individuals with vPS, 2) identify candidate genes for vPS, and 3) identify genes and pathways with high variant burden in individuals with vPS. Results of our study could impact genetic testing recommendations for infants and children with a new diagnosis of vPS. Earlier diagnosis of genetic disorders and understanding how genetic variants contribute to pathogenesis and ultimately outcomes of vPS can improve health and developmental outcomes by allowing anticipatory rather than reactionary guidance and management. PUBLIC HEALTH RELEVANCE: Congenital heart disease affects 1 in 100 live births and valvar pulmonary stenosis accounts for 8-10% of congenital heart disease. We propose whole genome sequencing in a large cohort of individuals with valvar PS in order to determine the prevalence of known genetic disorders, as well as identify candidate novel genes. This type of study and data is essential for being able to understand the genetic etiology of congenital heart disease.

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This page last reviewed on September 14, 2020