{"doi":"10.7554/elife.59554","title":"Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome","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.","journal":"eLife","year":2020,"id":62642,"datarank":1.254678287686187,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":0.6649044427775382,"self_endowment_contribution":0.5897738449086489,"citer_contribution":0.6649044427775382,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":36,"citers_with_citation_signal":32,"citers_with_endowment":32,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9275,"is_data_producer":true,"deposit_databanks":{"SRA":["SRX1736972"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":55675,"name":"Georg Vogler","orcid":"0000-0002-8303-3531","position":1,"is_corresponding":false},{"id":331344,"name":"Maria A Missinato","orcid":"0000-0001-9055-758X","position":2,"is_corresponding":false},{"id":331345,"name":"Xing Li","orcid":"0000-0003-2871-9415","position":3,"is_corresponding":false},{"id":331346,"name":"Tanja Nielsen","orcid":"0000-0002-2389-7514","position":4,"is_corresponding":false},{"id":331347,"name":"Xin-Xin I. Zeng","orcid":"0000-0002-2707-7759","position":5,"is_corresponding":false},{"id":331348,"name":"Almudena Martinez‐Fernandez","orcid":"0000-0003-2055-6308","position":6,"is_corresponding":false},{"id":331349,"name":"Stanley M. Walls","orcid":"0000-0002-5202-9927","position":7,"is_corresponding":false},{"id":331350,"name":"Anaïs Kervadec","orcid":"0000-0001-8105-6871","position":8,"is_corresponding":false},{"id":331351,"name":"James Kezos","orcid":"0000-0002-3581-7657","position":9,"is_corresponding":false},{"id":331352,"name":"Katja Birker","orcid":"0000-0003-4789-0971","position":10,"is_corresponding":false},{"id":332927,"name":"Jared M. Evans","orcid":null,"position":11,"is_corresponding":false},{"id":332928,"name":"Megan M. O’Byrne","orcid":null,"position":12,"is_corresponding":false},{"id":331353,"name":"Zachary C. Fogarty","orcid":"0000-0001-5588-3216","position":13,"is_corresponding":false},{"id":3672,"name":"André Terzic","orcid":"0000-0001-9210-009X","position":14,"is_corresponding":false},{"id":253479,"name":"Paul Grossfeld","orcid":"0000-0001-7215-3821","position":15,"is_corresponding":false},{"id":331354,"name":"Karen Ocorr","orcid":"0000-0003-2593-0119","position":16,"is_corresponding":false},{"id":256696,"name":"Timothy J. Nelson","orcid":null,"position":17,"is_corresponding":false},{"id":331355,"name":"Timothy M. Olson","orcid":"0000-0003-2716-9423","position":18,"is_corresponding":false},{"id":331356,"name":"Alexandre R. Colas","orcid":"0000-0001-8489-0570","position":19,"is_corresponding":false},{"id":55687,"name":"Rolf Bodmer","orcid":"0000-0001-9087-1210","position":20,"is_corresponding":false},{"id":331343,"name":"Jeanne L. Theis","orcid":"0000-0002-4494-8683","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-18T21:10:35.996198Z","pmid":"33006316","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}