CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.

中文翻译：

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CCDC88C 变异与局灶性癫痫和基因型-表型相关性相关

CCDC88C基因编码含有 88C 的卷曲螺旋结构域，对于神经发育过程中的细胞通讯至关重要。CCDC88C的变异引起先天性脑积水，有些还伴有癫痫发作。对于没有获得性病因的癫痫患者，我们进行了全外显子组测序（基于三​​重组）。在四例局灶性（部分）癫痫病例中发现了两种新的CCDC88C变体和两种双等位基因 CCDC88C 变体。这些变体在 gnomAD 群体中不存在或频率较低，多种计算算法预测这些变体具有破坏性。具有新发变异的患者表现为成人发病的癫痫，而具有双等位基因变异的患者表现为婴儿发病的癫痫。他们都对抗癫痫药物反应良好，并且没有癫痫发作。进一步分析表明，从头变体位于关键结构域，而一对双等位变体位于关键结构域之外，另一对配对变体具有非经典剪接和位于关键结构域的变体，表明亚分子效应。先天性脑积水相关的CCDC88C变异均被截短，而癫痫相关变异主要为错义，其比例明显高于先天性脑积水相关变异。CCDC88C可能与局灶性癫痫相关，且预后良好。表型变异的潜在机制可能与基因型和表型之间存在相关性。