Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive. We studied 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing. We identified biallelic variants in , encoding a protein of yet unknown function. Four affected individuals from 2 unrelated families segregated 2 homozygous frameshift variants in , whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of 2 affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process. Thus, our findings suggest that biallelic variants of cause a severe neurodevelopmental disorder.

中文翻译：

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ZFTRAF1 的双等位基因功能丧失变异导致神经发育障碍，伴有小头畸形和肌张力低下


神经发育障碍表现出临床和遗传异质性，因此表现出不同细胞通路组成部分的功能障碍；大多数人的确切病理机制仍然难以捉摸。我们研究了来自 3 个不相关家庭的 5 名受影响个体，这些个体均表现出整体发育迟缓、产后小头畸形和肌张力低下。我们使用外显子组测序和优先变体，随后使用免疫荧光、免疫印迹、pulldown 测定和 RNA 测序对这些变体进行表征。我们鉴定了 中的双等位变体，编码一种功能尚不清楚的蛋白质。来自 2 个不相关家族的 4 名受影响个体在 中分离出 2 个纯合移码变异，而在第三个家族中，检测到一个内含子剪接位点变异。我们在细胞水平上研究了 ZFTRAF1，并将其标记为不同人类细胞系中的核细胞质蛋白。 2 名受影响个体的成纤维细胞中完全不存在 ZFTRAF1。我们还鉴定了 110 种富含 mRNA 加工和自噬相关途径的相互作用蛋白。根据自噬标记物的分析，患者来源的成纤维细胞在蛋白质降解过程中表现出不规则性。因此，我们的研究结果表明，双等位基因变异会导致严重的神经发育障碍。