PDF(Pubmed)
Abstract：
Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (PUF60) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with PUF60-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient\'s missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as PUF60-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families.
摘要：
Poly（U）结合剪接因子60kDa基因（PUF60）中的杂合变体与Verheij综合征有关，具有结肠瘤的关键特征，身材矮小,骨骼异常,发育迟缓,腭畸形,先天性心脏和肾脏缺陷.这里,我们报告了5名来自PUF60相关疾病的不相关家庭的新患者，这些患者表现出具有三个截断变异的新遗传和临床表现。一个剪接位点变异可能减少蛋白质表达，和一个错觉变体。PUF60AlphaFold结构中患者错义变体的蛋白质建模揭示了与周围残基的极性键的丢失。所有患者都存在神经发育障碍，随着语音的变化，电机,认知，社会情绪和行为特征。新的表型扩展包括运动障碍以及反复呼吸道的免疫学发现，泌尿和耳部感染，特应性疾病,和皮肤异常。根据最近的生物和细胞研究，我们讨论了PUF60在感染和不感染免疫中的作用。由于我们的五名患者的表型不如经典Verheij综合征严重，特别是没有关键特征，如结肠缺损或腭异常，我们建议重新分类为PUF60相关的多系统参与的神经发育障碍。这些发现将有助于患者和家庭的遗传咨询。
