Shared segment analysis and next-generation sequencing implicates the retinoic acid signaling pathway in Total Anomalous Pulmonary Venous Return (TAPVR)

Dustin Nash, Cammon B. Arrington, Brett J. Kennedy, Mark Yandell, Wilfred Wu, Wenying Zhang, Stephanie Ware, Lynn B. Jorde, Peter J. Gruber, H. Joseph Yost, Neil E. Bowles, Steven B. Bleyl

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0131514
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 29 2015
Externally publishedYes

Fingerprint

Scimitar Syndrome
retinoic acid
Tretinoin
Genes
lungs
Retinol-Binding Proteins
retinol-binding protein
genes
Sequence Analysis
sequence analysis
Chromosomes, Human, Pair 12
Congenital Heart Defects
Zebrafish
Functional analysis
Danio rerio
single nucleotide polymorphism
vitamin A
Single Nucleotide Polymorphism
Chromosomes
Polymorphism

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Shared segment analysis and next-generation sequencing implicates the retinoic acid signaling pathway in Total Anomalous Pulmonary Venous Return (TAPVR). / Nash, Dustin; Arrington, Cammon B.; Kennedy, Brett J.; Yandell, Mark; Wu, Wilfred; Zhang, Wenying; Ware, Stephanie; Jorde, Lynn B.; Gruber, Peter J.; Yost, H. Joseph; Bowles, Neil E.; Bleyl, Steven B.

In: PLoS One, Vol. 10, No. 6, e0131514, 29.06.2015.

Research output: Contribution to journalArticle

Nash, D, Arrington, CB, Kennedy, BJ, Yandell, M, Wu, W, Zhang, W, Ware, S, Jorde, LB, Gruber, PJ, Yost, HJ, Bowles, NE & Bleyl, SB 2015, 'Shared segment analysis and next-generation sequencing implicates the retinoic acid signaling pathway in Total Anomalous Pulmonary Venous Return (TAPVR)', PLoS One, vol. 10, no. 6, e0131514. https://doi.org/10.1371/journal.pone.0131514
Nash, Dustin ; Arrington, Cammon B. ; Kennedy, Brett J. ; Yandell, Mark ; Wu, Wilfred ; Zhang, Wenying ; Ware, Stephanie ; Jorde, Lynn B. ; Gruber, Peter J. ; Yost, H. Joseph ; Bowles, Neil E. ; Bleyl, Steven B. / Shared segment analysis and next-generation sequencing implicates the retinoic acid signaling pathway in Total Anomalous Pulmonary Venous Return (TAPVR). In: PLoS One. 2015 ; Vol. 10, No. 6.
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