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Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning

Khalid A Fakhro1, Murim Choi, Stephanie M Ware

  • 1Department of Genetics, The Howard Hughes Medical Institute,Yale University School of Medicine, New Haven, CT 06520, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 2, 2011
PubMed

Insights

Genetic analysis reveals rare copy number variations in heterotaxy (Htx), a congenital heart defect. This study identifies novel genes crucial for left-right body patterning, advancing understanding of Htx and reproductive fitness disorders.

Area of Science:

  • Human Genetics
  • Developmental Biology
  • Congenital Heart Disease Research

Background:

  • Dominant genetic diseases with high locus heterogeneity pose challenges for gene discovery due to the need for large populations.
  • Heterotaxy (Htx), a congenital heart disease linked to left-right (LR) body patterning abnormalities, presents features consistent with this challenge.
  • Model systems can aid in identifying specific genes involved in complex genetic disorders like Htx.

Purpose of the Study:

  • To identify genetic factors contributing to heterotaxy (Htx) by analyzing copy number variations (CNVs).
  • To investigate the role of identified candidate genes in left-right (LR) body patterning using a Xenopus model.
  • To discover novel genes implicated in congenital heart disease and LR patterning.

Main Methods:

  • High-resolution genotyping of 262 Htx subjects and 991 controls to detect rare genic copy number variations.
  • In situ hybridization in Xenopus to assess gene expression patterns in the left-right organizer.
  • Morpholino knockdown in Xenopus embryos to evaluate the functional impact of candidate genes on LR development and pitx2 expression.

Main Results:

  • A significant twofold excess of rare genic CNVs was observed in Htx subjects compared to controls (14.5% vs. 7.4%, P = 1.5 × 10(-4)).
  • Of 38 smaller CNVs affecting 61 genes, 22 had Xenopus orthologs, with 7 showing enrichment in the LR organizer.
  • Knockdown of five candidate genes (NEK2, ROCK2, TGFBR2, GALNT11, NUP188) in Xenopus disrupted LR development and pitx2 expression, with high specificity.

Conclusions:

  • Rare copy number variations are significantly associated with heterotaxy, implicating novel genes in its pathogenesis.
  • Several identified genes play critical roles in left-right body patterning, validated through Xenopus model system studies.
  • This research provides new genetic insights into heterotaxy and left-right patterning, potentially aiding future gene discovery for related disorders.

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