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PLoS One. 2015 Jun 29;10(6):e0131514. doi: 10.1371/journal.pone.0131514. eCollection 2015.

Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR).

Author information

1
Department of Pediatrics (Division of Cardiology), University of Utah School of Medicine, Salt Lake City, UT, United States of America.
2
Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
3
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.
4
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
5
Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT, United States of America.
6
Neurobiology and Anatomy, University of Utah, Salt Lake City, UT, United States of America.
7
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.

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.

PMID:
26121141
PMCID:
PMC4485409
DOI:
10.1371/journal.pone.0131514
[Indexed for MEDLINE]
Free PMC Article

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