De Novo 13q Deletions in Two Patients With Mild Anorectal Malformations as Part of VATER/VACTERL and VATER/VACTERL-Like Association and Analysis of εFNB2 in Patients With Anorectal Malformations
De Novo 13q Deletions in Two Patients With Mild Anorectal Malformations as Part of VATER/VACTERL and VATER/VACTERL-Like Association and Analysis of εFNB2 in Patients With Anorectal Malformations
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DOI：
10.1002/ajmg.a.36153
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发表时间：
2013-12-01
影响因子：
2
通讯作者：
Reutter, Heiko
中科院分区：
文献类型：
--
作者：
Dworschak, Gabriel C.;Draaken, Markus;Reutter, Heiko
肛门直肠畸形（ARMs）包括从轻度肛门异常到复杂泄殖腔畸形的广泛疾病。在40-50%的病例中，ARM发生在定义的遗传综合征或复杂的多发性先天性异常的背景下，如VATER/VALNL（椎骨缺陷[V]、ARM [A]、心脏缺陷[C]、气管食管瘘伴或不伴食管闭锁[TE]、肾畸形[R]和肢体缺陷[L]）相关。在这里，我们报告的鉴定在染色体13 q的缺失使用单核苷酸多态性为基础的阵列分析在两个轻度ARM患者的一部分，VATER/VALNL和VATER/VALNL样协会。这两个缺失重叠的ARM. Heterozygous Efnb 2小鼠敲除模型提出了轻度ARM的关键区域表明EFNB 2作为一个很好的候选基因在这一地区。我们的患者表现出轻微的ARM表型，与小鼠非常相似。我们对331例孤立性ARM或ARM作为VATER/VEGIL或VATER/VEGIL样关联的一部分的患者进行了EFNB 2基因的综合突变分析。然而，我们没有发现任何致病突变。鉴于EFNB 2作为ARM的候选基因的令人信服的论据，分析更大的样本和EFNB 2的功能相关的非编码区的筛选是必要的。总之，我们的报告强调了染色体13 q缺失与ARM的关联，这表明常规分子诊断检查应包括对这些缺失的搜索。尽管我们的突变筛查结果是阴性的，但我们仍然认为EFNB 2是一个有助于人类ARM发展的优秀候选基因。(c)2013 Wiley Periodicals，Inc.
Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40-50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism-based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL-like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL-like associations. However, we did not identify any disease-causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non-coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans. (c) 2013 Wiley Periodicals, Inc.