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

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 cong...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 7; p. 2915
Main Authors: Fakhro, Khalid A, Choi, Murim, Ware, Stephanie M, Belmont, John W, Towbin, Jeffrey A, Lifton, Richard P, Khokha, Mustafa K, Brueckner, Martina
Format: Journal Article
Language:English
Published: United States 15.02.2011
Subjects:
Animals
Body Patterning - genetics
Chromosome Aberrations
DNA Copy Number Variations - genetics
Gastrula - embryology
Gastrula - metabolism
Gene Knockdown Techniques
Genotype
Heart Defects, Congenital - genetics
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
In Situ Hybridization
N-Acetylgalactosaminyltransferases - genetics
Nuclear Pore Complex Proteins - genetics
Protein-Serine-Threonine Kinases - genetics
Receptors, Transforming Growth Factor beta - genetics
Transcription Factors - genetics
Transcription Factors - metabolism
Xenopus - genetics
Xenopus Proteins - genetics
Xenopus Proteins - metabolism
ISSN:1091-6490, 1091-6490
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1019645108