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Hum Mol Genet. 2019 Oct 18. pii: ddz213. doi: 10.1093/hmg/ddz213. [Epub ahead of print]

Model System Identification of Novel Congenital Heart Disease Gene Candidates: focus on RPL13.

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Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA.
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Baylor College of Medicine, Houston, TX, USA.


Genetics is a significant factor contributing to congenital heart disease (CHD), but our understanding of the genetic players and networks involved in CHD pathogenesis is limited. Here, we searched for de novo Copy Number Variations (CNVs) in a cohort of 167 CHD patients to identify DNA segments containing potential pathogenic genes. Our search focused on new candidate disease genes within 19 deleted de novo CNVs that did not cover known CHD genes. For this study, we developed an integrated high-throughput phenotypical platform to probe for defects in cardiogenesis and cardiac output in human iPSC-derived multipotent cardiac progenitor cells (MCPs) and, in parallel, in the Drosophila in vivo heart model. Notably, knockdown in MCPs of RPL13, a ribosomal gene and SON, an RNA splicing cofactor, reduced proliferation and differentiation of cardiomyocytes, while increasing fibroblasts. In the fly, heart-specific RpL13 knockdown, predominantly at embryonic stages, resulted in a striking 'no heart' phenotype. Knockdown of Son and Pdss2, among others, caused structural and functional defects, including reduced or abolished contractility, respectively. In summary, using a combination of human genetics and cardiac model systems, we identified new genes as candidates for causing human congenital heart disease, with particular emphasis on ribosomal genes, such as RPL13. This powerful, novel approach of combining cardiac phenotyping in human MCPs and in the in vivo Drosophila heart at high throughput will allow for testing large numbers of CHD candidates, based on patient genomic data, and for building upon existing genetic networks involved in heart development and disease.


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