Format

Send to

Choose Destination
Genome Med. 2017 Oct 31;9(1):95. doi: 10.1186/s13073-017-0482-5.

Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns.

Author information

1
Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
3
Department of Paediatrics, Children's Hospital, Krankenhausstr. 26-30, 4020, Linz, Austria.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
5
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
6
Division of Cardiology, Seattle Children's Hospital, Seattle, WA, USA.
7
Pediatric Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA.
8
Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
9
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, and the Texas Heart Institute, Houston, TX, USA.
10
Texas Children's Hospital, Houston, TX, USA.
11
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. jbelmont@illumina.com.
12
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. jbelmont@illumina.com.
13
, 5200 Illumina Way, San Diego, CA, USA. jbelmont@illumina.com.

Abstract

BACKGROUND:

Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes.

METHODS:

Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs.

RESULTS:

Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio = 4.0, 95% confidence interval 2.5-6.5).

CONCLUSIONS:

Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

KEYWORDS:

Cardiac malformation; Congenital heart disease; Developmental disorder; Rare disease; Whole exome sequence

PMID:
29089047
PMCID:
PMC5664429
DOI:
10.1186/s13073-017-0482-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center