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Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning
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Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning
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Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning
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Journal Article
Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning
2011
Overview
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 genie copy number variations in Htx (14.5% vs. 7.4%, P = 1.5x10⁻⁴). 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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ Cilia
/ DNA Copy Number Variations - genetics
/ Embryos
/ Fitness
/ Fluorescence in situ hybridization
/ Frogs
/ Genes
/ Genotype
/ Heart Defects, Congenital - genetics
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humans
/ loci
/ Mutation
/ N-Acetylgalactosaminyltransferases - genetics
/ Nuclear Pore Complex Proteins - genetics
/ patients
/ Protein-Serine-Threonine Kinases - genetics
/ Receptors, Transforming Growth Factor beta - genetics
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Xenopus
