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Study Description

The Gabriella Miller Kids First Pediatric Research Program (Gabriella Miller Kids First Pediatric Research Program) (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both, childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions.

Clinical and genetic sequence data obtained through Kids First funding is available through dbGaP and will be accessible through the Kids First Data Resource. The Kids First Data Resource, being developed during fiscal year 2017, will catalog and curate genomic and phenotypic data from a wide range of childhood cancers and structural birth defects conditions and serve as a central portal where data and analysis tools will be readily accessible to promote comprehensive and cross-cutting research and collaboration.

The Kids First study of nonsyndromic orofacial cleft birth defects (OFCs) is a whole genome sequencing study of 415 White parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, including collaborations with Dr. George Wehby of the University of Iowa, Dr. Jacqueline Hecht of the University of Texas, and Dr. Terri Beaty of Johns Hopkins University. Sequencing was done by the Washington University McDonell Genome Institute. The case in each of the Kids First trios has cleft lip (CL, Figure A below), cleft palate (CP, Figure B), or both (CL+CP, Figure C):

OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. 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). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. 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), and 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. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is to identify specific OFC risk variants in Whites by performing whole genome sequencing of parent-case trios.

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Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

Parent-child trios were included if the child has a cleft lip, cleft palate or both. Parents may or may not be affected. Only trios that self-identified as Caucasian were included.

Trios were excluded if one or more members of the trio did not have sufficient genomic DNA for the proposed whole genome sequencing. Trios were excluded if they did not self-identify as Caucasian.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Complete Genomics Assembler Version 1.2.0; File Format Version: July 2009 N/A N/A
Whole Genome Sequencing Illumina HiSeq X v2.5 N/A N/A
Study History

Orofacial clefts (OFCs), primarily cleft lip (CL) and cleft palate (CP), are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. 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).

In order to understand the etiology of these common birth defects, the investigators involved in this collaboration (University of Pittsburgh, University of Iowa,and Johns Hopkins University) have recruited large numbers of OFC case families and controls, recruited from many countries world-wide, over the course of many years of collaborative studies.

For the current Kids First project whole genome sequencing (WGS) will be performed in 415 case-parent trios of European descent included form the USA (Pennsylvania, Iowa, Texas, Missouri, Colorado) and international sites (Denmark, Hungary, Spain, Turkey).

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