Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome.

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. © 2020, Theis et al.

Citation

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 Colas, Rolf Bodmer. Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome. eLife. 2020 Oct 02;9

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PMID: 33006316

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