The Genetic Landscape of Familial Congenital Hydrocephalus
The Genetic Landscape of Familial Congenital Hydrocephalus
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DOI：
10.1002/ana.24964
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发表时间：
2017-06-01
影响因子：
11.2
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
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作者：
Shaheen, Ranad;Sebai, Mohammed Adeeb;Alkuraya, Fowzan S.
目的：先天性脑积水是一种重要的出生缺陷，其遗传学机制尚不完全清楚。到目前为止，只有4个基因是孟德尔病的致病基因，其中2个基因是X连锁的(L1CAM和AP1S2)，2个是常染色体隐性遗传(CCDC88C和MPDZ)，其中先天性脑积水是主要或唯一的临床特征。在这项研究中，我们的目的是确定家族性先天性脑积水的遗传病因，假设这些病例代表该疾病的孟德尔形式。方法：在适用的情况下，结合外显子组测序和位置图谱。结果：我们在大多数这些家系(21/27，78%)中发现了可能的原因突变，涉及16个基因，没有一个基因是X连锁的。纤毛病变和血糖异常是我们队列中最常见的先天性脑积水的病因(分别为19%和26%)。在1个有4个受影响成员的家庭中，我们发现了EML1的一个纯合子截断变异，我们认为这是先天性脑积水的一个新原因，而且它在皮质畸形中可能起到作用。同样，我们发现WDR81的隐性突变，以前与小脑性共济失调、智力低下和不平衡综合征2有关，会导致严重的先天性脑积水。此外，我们通过呈现与5个隐性等位基因相关的先天性脑积水的表型谱来证实先前报道的MPDZ候选基因。解释：我们的研究强调了隐性突变在家族性先天性脑积水中的重要性，并扩大了这种疾病的基因座异质性。
Objective: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease.Methods: Exome sequencing combined, where applicable, with positional mapping.Results: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles.Interpretation: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition.