Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome

Jeanne L. Theis, Georg Vogler, Maria A. Missinato, Xing Li, Tanja Nielsen, Xin Xin I. Zeng, Almudena Martinez-Fernandez, Stanley M. Walls, Anaïs Kervadec, James N. Kezos, Katja Birker, Jared M. Evans, Megan M. O’byrne, Zachary C. Fogarty, André Terzic, Paul Grossfeld, Karen Ocorr, Timothy J. Nelson, Timothy M. Olson, Alexandre R. ColasRolf Bodmer

Research output: Contribution to journalArticlepeer-review

Abstract

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

Original languageEnglish (US)
Article numbere59554
Pages (from-to)1-27
Number of pages27
JournaleLife
Volume9
DOIs
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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