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

Khalid A. Fakhro, Murim Choi, Stephanie Ware, John W. Belmont, Jeffrey A. Towbin, Richard P. Lifton, Mustafa K. Khokha, Martina Brueckner

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Dominant human genetic diseases that impair reproductive fitness and have high locus heterogeneity constitute a problem for gene discovery because the usual criterion of finding more mutations in specific genes than expected by chance may require extremely large populations. Heterotaxy (Htx), a congenital heart disease resulting from abnormalities in left-right (LR) body patterning, has features suggesting that many cases fall into this category. In this setting, appropriate model systems may provide a means to support implication of specific genes. By high-resolution genotyping of 262 Htx subjects and 991 controls, we identify a twofold excess of subjects with rare genic copy number variations in Htx (14.5% vs. 7.4%, P = 1.5 × 10-4). Although 7 of 45 Htx copy number variations were large chromosomal abnormalities, 38 smaller copy number variations altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated LR organizer (gastrocoel roof plate), a marked enrichment compared with 40 of 845 previously studied genes (sevenfold enrichment, P <10-6). Morpholino knockdown in Xenopus of Htx candidates demonstrated that five (NEK2, ROCK2, TGFBR2, GALNT11, and NUP188) strongly disrupted both morphological LR development and expression of pitx2, a molecular marker of LR patterning. These effects were specific, because 0 of 13 control genes from rare Htx or control copy number variations produced significant LR abnormalities (P = 0.001). These findings identify genes not previously implicated in LR patterning.

Original languageEnglish (US)
Pages (from-to)2915-2920
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number7
DOIs
StatePublished - Feb 15 2011
Externally publishedYes

Fingerprint

Heart Diseases
Genes
Xenopus
Body Patterning
Genetic Fitness
Morpholinos
Inborn Genetic Diseases
Medical Genetics
Genetic Association Studies
Chromosome Aberrations
In Situ Hybridization
Gene Expression
Mutation
Population

Keywords

  • Cardiac development
  • Embryo
  • Xenopus tropicalis

ASJC Scopus subject areas

  • General

Cite this

Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. / Fakhro, Khalid A.; Choi, Murim; Ware, Stephanie; Belmont, John W.; Towbin, Jeffrey A.; Lifton, Richard P.; Khokha, Mustafa K.; Brueckner, Martina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 7, 15.02.2011, p. 2915-2920.

Research output: Contribution to journalArticle

Fakhro, Khalid A. ; Choi, Murim ; Ware, Stephanie ; Belmont, John W. ; Towbin, Jeffrey A. ; Lifton, Richard P. ; Khokha, Mustafa K. ; Brueckner, Martina. / Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 7. pp. 2915-2920.
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