PUBLICATION

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

Authors
Nash, D., Arrington, C.B., Kennedy, B.J., Yandell, M., Wu, W., Zhang, W., Ware, S., Jorde, L.B., Gruber, P.J., Yost, H.J., Bowles, N.E., Bleyl, S.B.
ID
ZDB-PUB-150630-3
Date
2015
Source
PLoS One   10: e0131514 (Journal)
Registered Authors
Yost, H. Joseph
Keywords
Zebrafish, Embryos, Morpholino, Retinoic acid, Vitamin A, Genomic databases, Retinoic acid signaling cascade, Retinoid signaling
MeSH Terms
  • Animals
  • Chromosomes, Human, Pair 12/genetics
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Frequency/genetics
  • Gene Knockdown Techniques
  • Genetic Variation
  • Heart/embryology
  • Heart/physiology
  • High-Throughput Nucleotide Sequencing/methods*
  • Humans
  • Male
  • Morpholinos/pharmacology
  • Pedigree
  • Scimitar Syndrome/genetics*
  • Signal Transduction*
  • Software
  • Tretinoin/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
26121141 Full text @ PLoS One
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping