The complex genetics of hypoplastic left heart syndrome. Nat Genet 2017 Jul;49(7):1152-1159
Date
05/23/2017Pubmed ID
28530678Pubmed Central ID
PMC5737968DOI
10.1038/ng.3870Scopus ID
2-s2.0-85021771894 (requires institutional sign-in at Scopus site) 143 CitationsAbstract
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.
Author List
Liu X, Yagi H, Saeed S, Bais AS, Gabriel GC, Chen Z, Peterson KA, Li Y, Schwartz MC, Reynolds WT, Saydmohammed M, Gibbs B, Wu Y, Devine W, Chatterjee B, Klena NT, Kostka D, de Mesy Bentley KL, Ganapathiraju MK, Dexheimer P, Leatherbury L, Khalifa O, Bhagat A, Zahid M, Pu W, Watkins S, Grossfeld P, Murray SA, Porter GA Jr, Tsang M, Martin LJ, Benson DW, Aronow BJ, Lo CWMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Aorta
CRISPR-Cas Systems
Chromosome Mapping
Chromosomes, Human
Disease Models, Animal
Exome
Female
Gene Editing
Gene Knockout Techniques
Genetic Heterogeneity
Heart Ventricles
Humans
Hypoplastic Left Heart Syndrome
Male
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mutation
Mutation, Missense
Myocytes, Cardiac
Penetrance
Sequence Alignment
Sequence Homology, Amino Acid
Ventricular Outflow Obstruction
Zebrafish