We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome.

中文翻译：

---

FBRSL1中的从头突变引起一种新型的可识别的畸形和智力残疾综合症。

我们报告了三个不相关的儿童的FBRSL1特定外显子的从头突变形式，这些患者有呼吸功能不全，产后生长受限，小头畸形，整体发育迟缓和其他畸形。FBRSL1的功能很大程度上未知。有趣的是，FBRSL1旁系AUTS2中的突变导致智障综合征（AUTS2综合征）。我们确定了人类FBRSL1转录本，并通过蛋白质印迹分析描述了蛋白质编码形式，以及通过免疫细胞化学染色对细胞进行了定位。所有检测到的突变都会影响两个短的N末端同工型，它们在胎儿组织中普遍存在。下一个，我们在非洲爪蟾胚胎中进行了Fbrsl1敲低，以探索Fbrsl1在发育过程中的作用，并检测出颅面异常和神经突生长的异常。非洲爪蟾胚胎的异常表型可以用人的N末端同工型挽救，而从患者身上分离出的长突变体和含有p.Gln163 *突变的N末端同工型不能挽救由Fbrsl1耗竭引起的颅面缺陷。基于这些数据，我们建议在胚胎发生过程中的关键时间点验证FBRSL1的N末端亚型的破坏导致迄今未描述的复杂神经发育综合征。而从患者身上分离出的长突变体和含有p.Gln163 *突变的N端异构体无法挽救由Fbrsl1耗尽引起的颅面缺陷。基于这些数据，我们建议在胚胎发生期间的关键时间点验证FBRSL1的N端亚型的破坏导致迄今未描述的复杂神经发育综合征。从患者身上分离出的长突变体和含有p.Gln163 *突变的N端异构体无法挽救因Fbrsl1耗尽而引起的颅面缺陷。基于这些数据，我们建议在胚胎发生过程中的关键时间点验证FBRSL1的N末端亚型的破坏导致迄今未描述的复杂神经发育综合征。