The complex genetics of hypoplastic left heart syndrome

Liu, X., Yagi, H., Saeed, S., Bais, A.S., Gabriel, G.C., Chen, Z., Peterson, K.A., Li, Y., Schwartz, M.C., Reynolds, W.T., Saydmohammed, M., Gibbs, B., Wu, Y., Devine, W., Chatterjee, B., Klena, N.T., Kostka, D., de Mesy Bentley, K.L., Ganapathiraju, M.K., Dexheimer, P., Leatherbury, L., Khalifa, O., Bhagat, A., Zahid, M., Pu, W., Watkins, S., Grossfeld, P., Murray, S.A., Porter, G.A., Tsang, M., Martin, L.J., Woodrow Benson, D., Aronow, B.J., Lo, C.W.
Nature Genetics   49(7): 1152-1159 (Journal)
Registered Authors
Lo, Cecilia, Tsang, Michael
Congenital heart defects, Genetic association study, Organogenesis
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Aorta/embryology
  • CRISPR-Cas Systems
  • Chromosome Mapping
  • Chromosomes, Human/genetics
  • Disease Models, Animal
  • Exome
  • Female
  • Gene Editing
  • Gene Knockout Techniques
  • Genetic Heterogeneity*
  • Heart Ventricles/embryology
  • Humans
  • Hypoplastic Left Heart Syndrome/genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation
  • Mutation, Missense
  • Myocytes, Cardiac/pathology
  • Penetrance
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Ventricular Outflow Obstruction/genetics
  • Zebrafish/genetics
28530678 Full text @ Nat. Genet.
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.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes