Pediatric Cardiology

, Volume 39, Issue 6, pp 1069–1081 | Cite as

The Genetic Landscape of Hypoplastic Left Heart Syndrome

  • Hisato Yagi
  • Xiaoqin Liu
  • George C. Gabriel
  • Yijen Wu
  • Kevin Peterson
  • Stephen A. Murray
  • Bruce J. Aronow
  • Lisa J. Martin
  • D. Woodrow Benson
  • Cecilia W. Lo
Riley Symposium


Hypoplastic left heart syndrome (HLHS) is one of the most lethal congenital heart defects, and remains clinically challenging. While surgical palliation allows most HLHS patients to survive their critical heart disease with a single-ventricle physiology, many will suffer heart failure, requiring heart transplantation as the only therapeutic course. Current paradigm suggests HLHS is largely of hemodynamic origin, but recent findings from analysis of the first mouse model of HLHS showed intrinsic cardiomyocyte proliferation and differentiation defects underlying the left ventricular (LV) hypoplasia. The findings of similar defects of lesser severity in the right ventricle suggest this could contribute to the heart failure risks in surgically palliated HLHS patients. Analysis of 8 independent HLHS mouse lines showed HLHS is genetically heterogeneous and multigenic in etiology. Detailed analysis of the Ohia mouse line accompanied by validation studies in CRISPR gene-targeted mice revealed a digenic etiology for HLHS. Mutation in Sap130, a component of the HDAC repressor complex, was demonstrated to drive the LV hypoplasia, while mutation in Pcdha9, a protocadherin cell adhesion molecule played a pivotal role in the valvular defects associated with HLHS. Based on these findings, we propose a new paradigm in which complex CHD such as HLHS may arise in a modular fashion, mediated by multiple mutations. The finding of intrinsic cardiomyocyte defects would suggest hemodynamic intervention may not rescue LV growth. The profound genetic heterogeneity and oligogenic etiology indicated for HLHS would suggest that the genetic landscape of HLHS may be complex and more accessible in clinical studies built on a familial study design.


Congenital heart disease Hypoplastic left heart syndrome Genetics Mouse model Oligogenic etiology 



This work was supported by funding from NIH U01-HL098180, R01-HL132024, S10-OD010340 (CWL), and Children’s Heart Foundation (LJM and DWB) and Junior Cooperative Society (DWB).

Compliance with Ethical Standards

Conflict of interest

All authors declare no conflicts of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All studies were pursued under animal protocols approved by the University of Pittsburgh and the Jackson Laboratory Institutional Animal Care and Use Committees. All procedures performed in studies involving human participants were carried out with informed consent under a human study protocol approved by the University of Pittsburgh Institutional Review Board and in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hisato Yagi
    • 1
  • Xiaoqin Liu
    • 1
  • George C. Gabriel
    • 1
  • Yijen Wu
    • 1
  • Kevin Peterson
    • 3
  • Stephen A. Murray
    • 3
  • Bruce J. Aronow
    • 2
  • Lisa J. Martin
    • 4
  • D. Woodrow Benson
    • 5
  • Cecilia W. Lo
    • 1
  1. 1.Department of Developmental BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of Biomedical InformaticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  3. 3.The Jackson LaboratoryBar HaborUSA
  4. 4.Division of Human GeneticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  5. 5.Pediatric CardiologyMedical College of WisconsinMilwaukeeUSA

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