Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.

中文翻译：

---

NUP188 中的双等位基因功能丧失变异体会导致一种以神经、眼部和心脏异常为特征的可识别综合征。


核孔蛋白 (NUP) 是核孔复合物的重要组成部分，可调节大分子的核细胞质运输。 NUP 基因的致病性变异与多种遗传性人类疾病有关，其中包括一些进行性神经退行性疾病。我们提出了六名受影响的个体，其 NUP188 具有双等位基因截短变异，并且具有惊人相似的表型和临床过程，代表了一种可识别的遗传综合征；这些人来自四个没有血缘关系的家庭。主要临床特征包括先天性白内障、肌张力低下、产前脑室扩大、白质异常、胼胝体发育不全、先天性心脏缺陷和中枢性通气不足。典型的畸形特征包括小睑裂、宽鼻梁和鼻子、小下颌和指异常。所有受影响的人均因呼吸衰竭而死亡，其中五人在一岁内死亡。受影响个体的成纤维细胞中蛋白质的核输入减少，支持可能的疾病机制。果蝇中 CRISPR 介导的 NUP188 敲除揭示了运动缺陷和癫痫易感性，部分重现了受影响个体中观察到的神经表型。 NUP188 的去除还导致异常的树突平铺，表明 NUP188 在树突发育中的潜在作用。其中两个 NUP188 致病性变异在 gnomAD 的德系犹太人群体中富集，我们通过对 3,225 名健康德系犹太人的国际抽样进行单独的目标群体筛查证实了这一发现。 综上所述，我们的结果表明，双等位基因功能丧失的 NUP188 变异体存在于隐性遗传综合征中，其特征是独特的神经、眼科和面部表型。