Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.
Hum Genomics. 2023 Mar 2;17(1):16. doi: 10.1186/s40246-023-00464-w.
Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.
We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.
In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.
Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.
先天性脑积水的特征是脑室扩大，即脑室扩张，被认为是由于脑脊液（CSF）平衡失调所致。原发性先天性脑积水是产前发病且无其他原发性病因（如脑出血）的病例亚组。已发表的系列报告显示，仅有少数病例存在孟德尔病因。在这项研究中，我们分析了 PCH 患者的外显子组数据，以寻找新的致病基因，并探讨了 PCH 可能存在潜在的寡基因遗传模式。
我们对 28 名无亲缘关系的 PCH 先证者进行了外显子组测序，其中 12 名来自至少有 2 名受影响兄弟姐妹的家族，9 名有亲缘关系，从而增加了遗传原因的贡献。首先分析患者外显子组数据中罕见（MAF<0.005）的传递或新生变异。通过主成分分析确定无亲缘关系的 PCH 患者和对照人群的群体分层，并使用 Mahalanobis 距离 5%作为截断值确定离群值。通过突变负担测试分析与纤毛相关的生物基因（SYScilia 数据库）的患者和对照外显子组数据。
在 18%的先证者中，我们确定了一个已知脑积水基因的致病（致病性或可能致病性）变异，包括以前未报道过的孤立性 PCH 相关的产后、综合征性脑积水基因。在另外 11%的患者中，我们发现了新的候选基因的突变。通过突变负担测试，我们发现 PCH 患者的编码原发性纤毛蛋白的基因存在显著的遗传变异负担，与对照相比。
我们的研究证实了孟德尔突变在 PCH 中的低贡献，并报告了 PCH 是一些已知的综合征性、产后性脑积水相关基因的表型表现。此外，本研究确定了新的孟德尔候选基因，并提供了证据表明原发性纤毛在 PCH 中存在寡基因遗传。
