Dataset Information

The complex genetics of hypoplastic left heart syndrome

ABSTRACT: Congenital heart disease (CHD) is a prevalent birth defect affecting up to 1% of live births. While a genetic etiology is indicated by increased recurrence risk and association with chromosomal abnormalities, the genetics of CHD is poorly understood and likely complex. Here we show hypoplastic left heart syndrome (HLHS), a severe CHD with high morbidity/mortality, has a multigenic etiology. Analysis of 8 HLHS mutant mouse lines recovered from a large-scale mutagenesis screen showed no mutations are shared in common. In the *Ohia* mouse line, mutations in 2 genes, *Pcdha9*/*Sap130*, act synergistically to cause HLHS. Cardiomyocyte proliferation and differentiation defects likely act in concert with valve abnormalities to cause HLHS. Network analysis of mutations recovered in HLHS mice and 68 HLHS patients point to Notch signaling disruption, a pathway previously implicated in HLHS. These findings demonstrate large-scale mutagenesis is an effective systems approach for interrogating the complex genetics of human diseases. SUBMITTER_CITATION: Journal: Nature Genetics Title: The complex genetics of hypoplastic left heart syndrome Author names: Xiaoqin Liu1, Hisato Yagi1, Shazina Saeed1, Abha S. Bais1, George C. Gabriel1, Zhaohan Chen1, Kevin A. Peterson4, You Li1, Molly C. Schwartz1, William T. Reynolds1, Manush Saydmohammed1, Brian Gibbs1, Yijen Wu1, William Devine1, Bishwanath Chatterjee1, Nikolai T. Klena1, Dennis Kostka1, Karen L. de Mesy Bentley5, Madhavi K.Ganapathiraju2, Phillip Dexheimer11, Linda Leatherbury7, Omar Khalifa1, Anchit Bhagat1, Maliha Zahid1, William Pu8, Simon Watkins3, Paul Grossfeld9, Stephen Murray4, George A. Porter, Jr.6, Michael Tsang1, Lisa J.Martin10, D.Woodrow.Benson12, Bruce J. Aronow11, Cecilia W. Lo1

ORGANISM(S): Mus musculus

PROVIDER: GSE77799 | GEO | 2017/04/13

SECONDARY ACCESSION(S): PRJNA311577

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating that impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in another familial CHD case of HLHS proband we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC-CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play critical roles in cardiogenesis and constitute an emerging novel class of gene candidates likely involved in HLHS and other CHDs.

Dataset Information

The complex genetics of hypoplastic left heart syndrome

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure