biostudies-literatureTheis JLTodd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome at Mayo Clinic FoundationNIA NIH HHSNHLBI NIH HHSNational Institutes of HealthNIH HHSe59554https://www.ebi.ac.uk/biostudies/studies/S-EPMC7581429biostudies-literatureUnknown9Congenital 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 <i>Drosophila</i> and zebrafish hearts revealed that LDL receptor-related protein <i>LRP2</i> 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,eLifePatient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome.PMC7581429HL054732SAN-233970R21 AG061598R01 HL132241R01 HL054732R01 HL153645R01 HL148827Bodmer RNelson TJMissinato MAWalls SMColas ARTheis JLMartinez-Fernandez AZeng XIOcorr KFogarty ZCKezos JNOlson TMVogler GBirker KLi XNielsen TEvans JMGrossfeld PTerzic AO'Byrne MMKervadec AfalsePatient-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 <i>Drosophila</i> and zebrafish hearts revealed that LDL receptor-related protein <i>LRP2</i> 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,2020-01-01T00:00:00Z2020 Oct2026-05-03T00:21:11.669Z2020-10-29T15:57:25ZS-EPMC75814293300631610.7554/eLife.59554