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Rare copy number variants contribute to congenital left-sided heart disease

Marc-Phillip Hitz1, Louis-Philippe Lemieux-Perreault, Christian Marshall

  • 1Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, Université de Montréal, Montréal, Québec, Canada.

Plos Genetics
|September 13, 2012
PubMed

Insights

This study identifies new genetic variations linked to left-sided congenital heart disease (CHD). These copy number variations (CNVs) suggest a role for disrupted angiogenesis in a subset of CHD cases.

Area of Science:

  • Genetics
  • Cardiology
  • Developmental Biology

Background:

  • Left-sided congenital heart disease (CHD) is a spectrum of conditions with significant infant mortality and adult implications.
  • While highly heritable, the genetic causes of left-sided CHD remain largely unknown.
  • Structural genomic variations, such as copy number variations (CNVs), are implicated in complex diseases.

Purpose of the Study:

  • To investigate the impact of structural genomic variation on left-sided CHD.
  • To identify novel genetic determinants contributing to left-sided CHD pathogenesis.
  • To explore the relationship between CNVs and angiogenesis in left-sided CHD.

Main Methods:

  • A family-based study comparing 59 multiplex families (464 individuals) and 8 trios with 1,582 controls.
  • Identification and analysis of inherited and de novo copy number variations (CNVs).
  • Bioinformatic filtering and gene prioritization to identify candidate genes for left-sided CHD.

Main Results:

  • Identified 73 unique inherited or de novo CNVs in 54 individuals within the left-sided CHD cohort.
  • Discovered 25 new candidate genes for left-sided CHD pathogenesis, including SMC1A, MFAP4, and CTHRC1.
  • Found that unique CNVs in affected individuals strongly implicate a role in at least 10% of left-sided CHD cases.
  • Demonstrated a significant association between CNV gene content and angiogenesis.

Conclusions:

  • Both co-segregating and de novo CNVs associate with left-sided CHD in a complex manner.
  • A subset of left-sided CHD may stem from broader genetic disruptions in angiogenesis and vascular biology.
  • This study highlights the importance of structural genomic variation in understanding left-sided CHD.

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