Journal article
Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
Human genetics, Vol.139(2), pp.215-226
2020
DOI: 10.1007/s00439-019-02099-1
PMCID: PMC6981325
PMID: 31848685
Abstract
Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent–offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case–parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.
Details
- Title: Subtitle
- Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
- Creators
- Nandita Mukhopadhyay - University of PittsburghMadison Bishop - Emory UniversityMichael Mortillo - Emory UniversityPankaj Chopra - Emory UniversityJacqueline B. Hetmanski - Johns Hopkins UniversityMargaret A. Taub - Johns Hopkins UniversityLina M. Moreno - University of IowaLuz Consuelo Valencia-Ramirez - Fundación Clínica Noel (http://www.clinicanoel.org.co/), Medellín, Colombia.Claudia Restrepo - Fundación Clínica Noel (http://www.clinicanoel.org.co/), Medellín, Colombia.George L. Wehby - University of IowaJacqueline T. Hecht - The University of Texas Health Science Center at HoustonFrederic Deleyiannis - UC Health Plastic and Reconstructive SurgeryAzeez Butali - University of IowaSeth M. Weinberg - University of PittsburghTerri H. Beaty - Johns Hopkins UniversityJeffrey C. Murray - University of IowaElizabeth J. Leslie - Emory UniversityEleanor Feingold - University of PittsburghMary L. Marazita - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.139(2), pp.215-226
- DOI
- 10.1007/s00439-019-02099-1
- PMID
- 31848685
- PMCID
- PMC6981325
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Publisher
- Springer Berlin Heidelberg
- Grant note
- R01-DE016148; R03-DE026469; R01-DE016148; R03-DE026469; U01-DD000295; R01-DE014581; R01-DE011931; R01-DE014667; R00-DE025060; R01-DE012472; R21-DE016930 / National Institutes of Health (http://dx.doi.org/10.13039/100000002)
- Language
- English
- Date published
- 2020
- Academic Unit
- Preventive and Community Dentistry; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984353934702771
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