title: Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR).
abstract: Most isolated congenital heart defects are thought to be sporadic and are often ascribed to multifactorial mechanisms with poorly understood genetics. Total Anomalous Pulmonary Venous Return (TAPVR) occurs in 1 in 15,000 live-born infants and occurs either in isolation or as part of a syndrome involving aberrant left-right development. Previously, we reported causative links between TAVPR and the PDGFRA gene. TAPVR has also been linked to the ANKRD1/CARP genes. However, these genes only explain a small fraction of the heritability of the condition. By examination of phased single nucleotide polymorphism genotype data from 5 distantly related TAPVR patients we identified a single 25 cM shared, Identical by Descent genomic segment on the short arm of chromosome 12 shared by 3 of the patients and their obligate-carrier parents. Whole genome sequence (WGS) analysis identified a non-synonymous variant within the shared segment in the retinol binding protein 5 (RBP5) gene. The RBP5 variant is predicted to be deleterious and is overrepresented in the TAPVR population. Gene expression and functional analysis of the zebrafish orthologue, rbp7, supports the notion that RBP5 is a TAPVR susceptibility gene. Additional sequence analysis also uncovered deleterious variants in genes associated with retinoic acid signaling, including NODAL and retinol dehydrogenase 10. These data indicate that genetic variation in the retinoic acid signaling pathway confers, in part, susceptibility to TAPVR.
authors.affiliation: Department of Pediatrics (Division of Cardiology), University of Utah School of Medicine, Salt Lake City, UT, United States of America.
authors.forename: Dustin
authors.initials: D
authors.lastname: Nash
authors.affiliation: Department of Pediatrics (Division of Cardiology), University of Utah School of Medicine, Salt Lake City, UT, United States of America.
authors.forename: Cammon B
authors.initials: CB
authors.lastname: Arrington
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Kennedy
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America; USTAR Center for Genetic Discovery, Salt Lake City, UT, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Wu
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Wenying
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ware
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.affiliation: Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.affiliation: Neurobiology and Anatomy, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
authors.affiliation: Department of Pediatrics (Division of Cardiology), University of Utah School of Medicine, Salt Lake City, UT, United States of America.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.affiliation: Department of Pediatrics (Division of Cardiology), University of Utah School of Medicine, Salt Lake City, UT, United States of America; Clinical Genetic Institute, Intermountain Healthcare, Salt Lake City, UT, United States of America.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
mesh_terms: D000818:Animals; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005787:Gene Frequency / Q000235:genetics; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006321:Heart / Q000196:embryology / Q000502:physiology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D060172:Morpholinos / Q000494:pharmacology; D010375:Pedigree; D012587:Scimitar Syndrome / Q000235:genetics*; D015398:Signal Transduction; D012984:Software; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D060172:Morpholinos; D029961:Zebrafish Proteins; D014212:Tretinoin