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Proc Natl Acad Sci U S A. February 15, 2011; 108 (7): 2915-20.

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

Fakhro KA , Choi M , Ware SM , Belmont JW , Towbin JA , Lifton RP , Khokha MK , Brueckner M .

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.

PubMed ID: 21282601
PMC ID: PMC3041108
Article link: Proc Natl Acad Sci U S A.
Grant support: R01DE018824 NIDCR NIH HHS, R01DE18825 NIDCR NIH HHS, R01HD045789 NICHD NIH HHSHoward Hughes Medical Institute , R01 DE018824 NIDCR NIH HHS, R01 HD045789 NICHD NIH HHS , R01 HL093280 NHLBI NIH HHS , R01 DE018825 NIDCR NIH HHS

Genes referenced: aldh1a1 cryzl1 dnah9 galnt11 gdf7 greb1 grik1 ift88 igfbp5 kyat1 laptm5 lrrc8a myh6 nek2 nup188 pdgfc pitx2 rho rho.2 rock2 rpsa runx2 smarcal1 tgfbr2.2 tpk1 trat1 tgfbr2

Morpholinos referenced: aldh1a1 MO1 ccbl1 MO1 cryzl1 MO1 dnah9 MO1 galnt11 MO1 gdf7 MO1 greb1 MO1 grik1 MO1 ift88 MO3 igfbp5 MO1 laptm5 MO1 lrrc8a MO1 myh6 MO1 nek2 MO1 nup188 MO1 pdgfc MO1 rock2 MO1 runx2 MO1 smarcal1 MO1 tgfbr2 MO1 tpk1 MO1 trat1 MO1
Disease Ontology references: visceral heterotaxy

External Resources: GO Terms referenced: heart looping [+]

Article Images: [+] show captions

Avidor-Reiss, 2004, Pubmed [+]

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