OBJECTIVE COL4A1 variant causes severe central nervous system (CNS) anomalies, including hydranencephaly. However, the pathogenic mechanism underlying the COL4A1 phenotype remains unclear. Here, we report de novo COL4A1 variants in four Japanese patients with typical or rare CNS involvement and exhibiting diverse phenotypes. METHODS We identified and enrolled four patients with white matter abnormalities and cerebral structural defects suggestive of cerebrovascular disease. Genetic analysis was performed using panel sequencing. RESULTS All the patients were perinatally asymptomatic during the infantile period but exhibited developmental delay and growth retardation later. All the patients exhibited CNS symptoms, including psychomotor disability, spastic paralysis, and epilepsy. Brain magnetic resonance imaging revealed hydranencephaly (n = 1), ventriculomegaly (n = 4) associated with cerebral hemorrhage, and atretic encephalocele (n = 1). Three patients had developed congenital cataract, while two had hematuria. We identified two COL4A1 missense variants [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] and two in frame variants [exon32:c.2603_2609delinsATCCTGA p.(Ala868_Gly870delinsAspProGlu), exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]. The in frame variants were associated with severe CNS anomalies, hydranencephaly, and severe ventriculomegaly. Atretic encephalocele has never been reported in individuals with COL4A1 variants. CONCLUSIONS Our findings suggest that COL4A1 variants cause variable CNS symptoms. Association between clinical phenotypes and each COL4A1 variant would clarify their underlying etiologies.

中文翻译：

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扩展 COL4A1 相关疾病的表型——四种新型变异

目标 COL4A1 变异导致严重的中枢神经系统 (CNS) 异常，包括脑积水。然而，COL4A1 表型的致病机制仍不清楚。在这里，我们报告了四名具有典型或罕见 CNS 受累并表现出不同表型的日本患者的 de novo COL4A1 变异。方法 我们确定并招募了四名患有脑血管疾病的白质异常和脑结构缺陷的患者。使用面板测序进行遗传分析。结果所有患者在婴儿期均无围产期症状，但后期出现发育迟缓和生长迟缓。所有患者均表现出中枢神经系统症状，包括精神运动障碍、痉挛性麻痹和癫痫。脑磁共振成像显示水脑畸形（n = 1），与脑出血相关的脑室扩大（n = 4）和闭锁性脑膨出（n = 1）。三名患者出现先天性白内障，两名患者出现血尿。我们确定了两个 COL4A1 错义变体 [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] 和两个框架中的变体 [exon32:c.2603_2609delinsATCCT8Glu780delinsATCCT8Glu870delinsATCCT870delinsAp.(Gly852Asp)] exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]。帧内变异与严重的中枢神经系统异常、脑积水和严重的脑室扩大有关。在具有 COL4A1 变异的个体中从未报道过闭锁性脑膨出。结论 我们的研究结果表明，COL4A1 变异会导致不同的 CNS 症状。临床表型与每个 COL4A1 变异之间的关联将阐明其潜在病因。