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Background: Congenital heart diseases, such as hypoplastic left heart syndrome (HLHS), are considered to have complex genetic underpinnings that are poorly understood. Here, an integrated multi-disciplinary approach was applied to identify novel genes and underlying mechanisms associated with HLHS. Methods: A family-based strategy was employed that coupled whole genome with RNA sequencing of patient-derived induced pluripotent stem cells (iPSCs) from an HLHS proband-parent trio to identify, prioritize and functionally evaluate candidate genes in model systems. Results: Consistent with the hypoplastic phenotype, the proband's iPSCs had reduced proliferation capacity. Mendelian inheritance modeling identified 10 genes with recessive rare variants and altered expression compared to the parents' iPSCs. siRNA/RNAi-mediated knockdown in generic human iPSC-derived cardiac progenitors and in the in vivo Drosophila heart model revealed that LDL receptor related protein LRP2 and apolipoprotein APOB are required for robust hiPSC-derived cardiomyocyte proliferation and Drosophila heart function, respectively, possibly involving an oligogenic mechanism via growth-promoting WNT and SHH signaling. Burden analysis of rare damaging variants in the 2 genes and 80 interacting partners in a cohort of 130 HLHS probands and 861 controls identified significant enrichment in LRP2 (p<0.001), a gene associated with poor clinical outcomes in 30% of cases. Conclusions: Collectively, this cross-functional genetic approach to complex congenital heart disease revealed disruption of LRP2 function as a novel genetic driver of HLHS, and hereby established a scalable approach to decipher the oligogenic underpinnings of maladaptive left heart development. ### Competing Interest Statement The authors have declared no competing interest.

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