학술논문
Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome
Document Type
article
Author
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
Source
eLife, Vol 9 (2020)
Subject
Language
English
ISSN
2050-084X
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 parents 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.