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首页> 外文期刊>American journal of medical genetics, Part A >The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle
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The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle

机译：ZIC3突变的表型谱包括孤立的大动脉d-转位和右室双出口

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摘要

Disease causing mutations for heterotaxy syndrome were first identified in the X-linked laterality gene, ZIC3. Mutations typically result in males with situs ambiguus and complex congenital heart disease; however affected females and one male with isolated d-transposition of the great arteries (d-TGA) have been reported. We hypothesized that a subset of patients with heart defects common to heterotaxy but without laterality defects would have ZIC3 mutations. We also sought to estimate the prevalence of ZIC3 mutations in sporadic heterotaxy. Patients with TGA (n=169), double outlet right ventricle (DORV; n=89), common atrioventricular canal (CAVC; n=41), and heterotaxy (n=54) underwent sequencing of ZIC3 exons. We tested 90 patients with tetralogy of Fallot (TOF) to correlate genotype with phenotype. Three potentially disease-related missense mutations were detected: c.49G>T (Gly17Cys) in a female with isolated DORV, c.98C>T (Ala33Val) in a male with isolated d-TGA, and c.841C>T (His281Tyr) in a female with sporadic heterotaxy. We also identified a novel insertion (CPFP333ins) in a family with heterotaxy. All were absent in 200 control patients and the 1000 Genomes Project (n=629). No significant mutations were found in patients with TOF. Functional studies demonstrated reduced transcriptional activity of the ZIC3 His281Tyr mutant protein. ZIC3 mutations were rarely identified in isolated DORV and d-TGA suggesting that a subset of DORV and d-TGA may fall within the spectrum of laterality defects. ZIC3 mutations were found in 3.7% of patients with sporadic heterotaxy; therefore testing should be considered in patients with heterotaxy.
机译：首先在X连锁偏向基因ZIC3中鉴定出导致异型综合征的致病突变。突变通常会导致男性出现情景矛盾和复杂的先天性心脏病;然而，据报道，受影响的雌性和雄性大动脉孤立地发生了d-转位（d-TGA）。我们假设一部分患有异位症常见但没有侧偏缺陷的心脏缺陷患者会出现ZIC3突变。我们还试图估计零星异位症中ZIC3突变的患病率。患有TGA（n = 169），双出口右心室（DORV; n = 89），房室总管（CAVC; n = 41）和异源性（n = 54）的患者接受了ZIC3外显子的测序。我们测试了90名患有法洛四联症（TOF）的患者，以将基因型与表型相关联。检测到三个潜在的与疾病相关的错义突变：女性中分离出DORV的c.49G> T（Gly17Cys），男性中分离出d-TGA的c.98C> T（Ala33Val）和c.841C> T（His281Tyr ），女性具有散发性异位症。我们还发现了一个具有异型家族的新型插入物（CPFP333ins）。 200例对照患者和1000个基因组计划（n = 629）中都没有。在TOF患者中未发现明显的突变。功能研究表明ZIC3 His281Tyr突变蛋白的转录活性降低。在分离的DORV和d-TGA中很少发现ZIC3突变，这表明DORV和d-TGA的一个子集可能落在侧向缺陷谱内。 3.7％的散发性异位患者中发现了ZIC3突变;因此，对于异位患者应考虑进行检查。

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