Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing
Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing
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全外显子组测序揭示前脑无裂畸形的复杂遗传模式
DOI：
10.1111/cge.12722
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发表时间：
2016
影响因子：
3.5
通讯作者：
Véronique David
中科院分区：
文献类型：
--
作者：
C. Mouden;C. Dubourg;W. Carré;S. Rose;C. Quélin;Linda Akloul;Houda Hamdi;G. Viot;H. Salhi;P. Darnault;S. Odent;V. Dupé;Véronique David
无前脑畸形(HPE)是最常见的先天性脑畸形，以前脑分裂受损和面部中线畸形为特征。14个基因的杂合突变与HPE有关，通常是从未受影响的父母那里遗传过来的，背后有复杂的遗传基础。现在发现，HPE可能是多个基因事件的组合导致的，而不是单一杂合突变造成的。为了探索这一假设，我们采用了完整的外显子组测序和有针对性的高通量测序方法来识别HPE受试者的突变。在这里，我们报告了两个HPE家系，其中两个突变与疾病有关。在第一个家系中，我们发现了两个患有白叶型和半叶型HPE的胎儿，涉及HPE的两个基因SHH和DISP1分别遗传自父亲和母亲。第二例报告的病例是一名9岁女孩的家庭，表现为大叶型HPE，在DISP1中存在两个复合杂合性突变。总之，这些双基因遗传和常染色体隐性遗传性HPE的病例表明，在一些家庭中，几个遗传事件是导致HPE的必要因素。这项研究突出了HPE遗传的复杂性，临床医生必须考虑到这一点，以改进HPE遗传咨询。
Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high‐throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi‐lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9‐year‐old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling.
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影响因子：
7
作者：
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通讯作者：
Haussler, D
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通讯作者：
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