| Literature DB >> 28530678 |
Xiaoqin Liu1, Hisato Yagi1, Shazina Saeed1, Abha S Bais1, George C Gabriel1, Zhaohan Chen1, Kevin A Peterson2, You Li1, Molly C Schwartz1, William T Reynolds1, Manush Saydmohammed1, Brian Gibbs1, Yijen Wu1, William Devine1, Bishwanath Chatterjee1, Nikolai T Klena1, Dennis Kostka1, Karen L de Mesy Bentley3, Madhavi K Ganapathiraju4, Phillip Dexheimer5, Linda Leatherbury6, Omar Khalifa1, Anchit Bhagat1, Maliha Zahid1, William Pu7, Simon Watkins8, Paul Grossfeld9, Stephen A Murray2, George A Porter10, Michael Tsang1, Lisa J Martin11, D Woodrow Benson12, Bruce J Aronow5, Cecilia W Lo1.
Abstract
Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR-Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD.Entities:
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Year: 2017 PMID： 28530678 PMCID： PMC5737968 DOI： 10.1038/ng.3870
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330