Hydrocephalus is one of the most common pathophysiological disabilities with a high mortality rate, which occurs both congenitally and acquired. It is estimated that genetic components are the etiology for up to 40% of hydrocephalus cases; however, causal mutations identified until now could only explain approximately 20% of congenital hydrocephalus (CH) patients, and most potential hydrocephalus-associated genes have yet to be determined. This study sought to find causal variations in a consanguineous family with four affected children diagnosed with hydrocephalus. In this study, we evaluated twenty-five members of an extended family consisting of a nuclear family with four affected children resulting from a consanguineous couple and eighteen of their relatives, including one hydrocephalus case. The mother of this family was experiencing her 15th week of pregnancy, and cytogenetic evaluation was performed using amniocentesis to identify fetal chromosomal abnormalities. We conducted whole-exome sequencing (WES) on the genomic DNA of the proband to detect the CH-causing variants, followed by confirmation and segregation analysis of the detected variant in the proband, fetus, and family members through Sanger sequencing. Following the bioinformatic analysis and data filtering, we found a homozygous variant [NM_001243766.2:c.74G>A:p.W25X] within the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene confirmed by Sanger sequencing in the proband and segregated with the hydrocephalus in the family. The variant was described as pathogenic and regarded as a nonsense-mediated mRNA decay (NMD) due to the premature stop codon, which results in a truncated protein. The results of the current study broadened the mutational gene spectrum of CH and our knowledge of the hydrocephalus etiology by introducing a novel homozygous variant within the POMGNT1 gene, which had never been previously reported solitary in these patients.

中文翻译：

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使用全外显子组测序在伊朗先天性脑积水家族中鉴定出 POMGNT1 基因的纯合致病性变异

脑积水是最常见的病理生理障碍之一，死亡率很高，有先天性和后天性两种。据估计，高达 40% 的脑积水病例的病因是遗传因素；然而，迄今为止发现的致病突变只能解释大约 20% 的先天性脑积水 (CH) 患者，并且大多数潜在的脑积水相关基因尚未确定。本研究旨在寻找一个有四名被诊断患有脑积水的儿童的近亲家庭中的因果变异。在这项研究中，我们评估了一个大家庭的 25 名成员，该大家庭由一个核心家庭和一对近亲夫妇所生的四名受影响的孩子及其十八名亲戚组成，其中包括一名脑积水病例。该家庭的母亲正在怀孕第15周，通过羊膜穿刺术进行细胞遗传学评估，以确定胎儿染色体异常。我们对先证者的基因组DNA进行全外显子组测序（WES），以检测引起CH的变异，然后通过桑格测序对先证者、胎儿和家庭成员中检测到的变异进行确认和分离分析。经过生物信息学分析和数据过滤，我们在蛋白质O-甘露糖β-1,2-N-乙酰氨基葡萄糖转移酶1（POMGNT1）基因中发现了一个纯合变异体[NM_001243766.2:c.74G>A:p.W25X]，经证实对先证者进行桑格测序，并与家系中的脑积水进行隔离。该变体被描述为致病性的，并被认为是由于过早终止密码子导致的无义介导的 mRNA 衰变 (NMD)，从而产生截短的蛋白质。本研究的结果通过在 POMGNT1 基因中引入一种新的纯合变异，拓宽了 CH 的突变基因谱，并扩大了我们对脑积水病因的了解，这种变异以前从未在这些患者中单独报道过。