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.
Highlights
Despite the high frequency with which congenital heart defects (CHD) occur and the great expense to society that these defects incur, the cause of most CHD remains unknown
The ANKRD1/CARP gene, which encodes a regulator of cardiac transcription, has been associated with Total Anomalous Pulmonary Venous Return (TAPVR) after a breakpoint near ANKRD1 was discovered in a TAPVR patient with a chromosome 10 and21 balanced translocation (t(10;21)) [4]
The damaging variant in retinol binding protein 5 (RBP5) did not reach genome-wide significance in our whole-genome analysis so without the shared segment mapping that is available through the use of the Utah Population Database (UPDB), it is unlikely we would have identified this variant as a candidate susceptibility for TAPVR
Summary
Despite the high frequency with which congenital heart defects (CHD) occur and the great expense to society that these defects incur, the cause of most CHD remains unknown One such CHD, Total Anomalous Pulmonary Venous Return (TAPVR), occurs in roughly 1 in 15,000 live-born infants [1] and is fatal if not surgically corrected within the first few days to weeks of life. The ANKRD1/CARP gene, which encodes a regulator of cardiac transcription, has been associated with TAPVR after a breakpoint near ANKRD1 was discovered in a TAPVR patient with a chromosome 10 and balanced translocation (t(10;21)) [4] Together these genes explain only a small fraction of the heritability of the condition
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