Supplementary Material for: X-Linked Hydrocephalus with New <b><i>L1CAM</i></b> Pathogenic Variants: Review of the Most Prevalent Molecular and Phenotypic Features

<b><i>Introduction:</i></b> The underlying molecular defects of congenital hydrocephalus are heterogeneous and many isolated forms of hydrocephalus remain unsolved at the molecular level. Congenital hydrocephalus in males associated with agenesis of the corpus callosum is a notable characteristic of <i>L1CAM</i> gene which is by far the most common genetic etiology of congenital hydrocephalus. <b><i>Methods and Results:</i></b> Sequencing of the <i>L1CAM</i> gene on 25 male patients/fetuses who had been presented with hydrocephalus revealed 6 patients and two fetuses with different hemizygous pathogenic variants. Our study identified 4 novel variants and 4 previously reported. The detection rate was 32%, and all the variants were shown to be maternally inherited. Nonsense variants were detected in 3 patients, while missense variants were detected in 2 patients. Frameshift, silent, and splicing variant, each was detected in 1 patient. The clinical manifestations of the patients are in line with those frequently observed including communicating hydrocephalus and agenesis of the corpus callosum. Moreover, rippled ventricles with subdural collection and asymmetry of ventricles after shunt operation were seen in 1 patient and 2 patients, respectively. In addition, abnormal basal ganglia were found in 4 patients which seems to be an additional distinct new finding. We also describe a patient with novel nonsense variant with the rare association of Hirschsprung’s disease. This patient displayed additionally multiple porencephalic cysts and encephalomalacia secondary to hemorrhage due to repeated infections after shunt operation. The patients with the missense variants showed long survival, while those with truncating variants showed poor prognosis. <b><i>Conclusion:</i></b> This report adds knowledge of novel pathogenic variants to the <i>L1CAM</i> variant database. Furthermore, we evaluated the clinical and imaging data of these patients.<b><i>引言：</i></b> 先天性脑积水的潜在分子缺陷具有异质性，且多数孤立性脑积水仍未明确其分子层面的致病机制。男性先天性脑积水合并胼胝体发育不全，是<i>L1CAM</i>基因相关疾病的显著特征，该基因也是目前已知的先天性脑积水最常见的遗传病因。 <b><i>方法与结果：</i></b> 本研究对25例表现为脑积水的男性患者/胎儿进行<i>L1CAM</i>基因测序，结果显示6例患者及2例胎儿携带不同的半合子致病性变异。本研究共鉴定出4种新发变异与4种既往已报道的变异，变异检出率为32%，且所有变异均为母系遗传。其中3例患者携带无义变异，2例患者携带错义变异；移码变异、沉默变异及剪接变异各在1例患者中检出。患者的临床表现与既往常见报道一致，包括交通性脑积水及胼胝体发育不全。此外，1例患者可见伴硬膜下积液的脑室波纹样改变，2例患者可见分流术后脑室不对称。此外，4例患者存在基底节异常，这一表现似乎是一项新的独特临床发现。本研究还报道了1例携带新发无义变异的患者，该患者合并罕见的赫希施普龙病（Hirschsprung’s disease）。该患者还出现了多处脑穿通畸形囊肿，以及因分流术后反复感染继发出血导致的脑软化症。携带错义变异的患者生存期较长，而携带截短变异的患者预后较差。 <b><i>结论：</i></b> 本研究为<i>L1CAM</i>基因变异数据库补充了新的致病性变异相关数据。此外，本研究还对上述患者的临床及影像学资料进行了分析评估。