Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.
Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.
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DOI：
10.1002/humu.22786
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发表时间：
2015-06
期刊：
影响因子：
3.9
通讯作者：
Spinner, Nancy B.
中科院分区：
文献类型：
--
作者：
Tsai, Ellen A.;Grochowski, Christopher M.;Falsey, Alexandra M.;Rajagopalan, Ramakrishnan;Wendel, Danielle;Devoto, Marcella;Krantz, Ian D.;Loomes, Kathleen M.;Spinner, Nancy B.
胆道闭锁是一种病因不明的小儿胆管疾病，以孤立和综合征的形式出现。影响心血管和胃肠道系统的偏侧性缺陷是BA综合征最常见的特征。大多数病例是散发的，尽管家族性病例的报告导致了一些患者遗传易感性的假设。我们发现了一个患有BA、旋转不良和下腔静脉中断的孩子，他的父亲表现为反位、多脾、全垂体功能减退和轻度畸形的面部特征。染色体微阵列分析表明，20号染色体上的一个277 kb的杂合性缺失，其中包括一个单一的基因，FOXA 2，在先证者和她的父亲。这种缺失被证实是父亲的新生。先证者和她的父亲有一个共同的异位症诊断，但他们也各自提出了各种其他问题。进一步的遗传筛查显示，先证者携带额外的蛋白质改变多态性（rs 1904589; p.His165Arg）的NODAL基因，不存在于父亲，这种变异已被证明是减少基因的表达。由于FOXA 2可能是NODAL表达的调节因子，我们认为FOXA 2单倍不足结合NODAL表达降低可能是该先证者BA综合征的原因。
Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2
作者：
Williams, P. G.;Wetherbee, J. J.;Hersh, J. H.
通讯作者：
Hersh, J. H.
影响因子：
5.1
作者：
Davenport, Mark;Tizzard, Sarah A.;Hadzic, Nedim
通讯作者：
Hadzic, Nedim
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C