The complex genetics of hypoplastic left heart syndrome

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Xiaoqin Liu1, Hisato Yagi1, Shazina Saeed1

  • 1Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Nature Genetics
|May 23, 2017
PubMed

Insights

Hypoplastic left heart syndrome (HLHS), a severe congenital heart defect (CHD), is genetically complex. This study identifies novel digenic gene combinations, like Sap130 and Pcdha9, causing HLHS, offering a new genetic paradigm.

Area of Science:

  • Genetics
  • Developmental Biology
  • Cardiology

Background:

  • Congenital heart disease (CHD) affects approximately 1% of newborns, with a complex genetic basis.
  • The genetic etiology of severe CHD, such as hypoplastic left heart syndrome (HLHS), remains largely undefined.
  • Sporadic occurrences suggest intricate genetic factors beyond simple inheritance patterns.

Purpose of the Study:

  • To identify the genetic causes of hypoplastic left heart syndrome (HLHS).
  • To investigate the multigenic and genetically heterogeneous nature of HLHS.
  • To establish a new paradigm for understanding the complex genetics of CHD.

Main Methods:

  • Utilized mouse forward genetics to isolate HLHS mutant mouse lines.
  • Employed CRISPR-Cas9 genome editing for gene validation in mice.
  • Developed mouse and zebrafish models to study gene function in HLHS pathogenesis.

Main Results:

  • Identified mutations in Sap130 and Pcdha9 as digenic causes of HLHS.
  • Found multigenic enrichment in human chromosomal regions associated with HLHS.
  • Observed Sap130 mediating left ventricular hypoplasia and Pcdha9 increasing aortic valve abnormalities in HLHS models.

Conclusions:

  • HLHS is a multigenic and genetically heterogeneous condition.
  • Novel genes, Sap130 and Pcdha9, contribute to HLHS development.
  • HLHS can result from combinatorial genetic interactions, advancing the understanding of CHD genetics.

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