PURA的从头突变最近被描述为导致PURA综合征,一种以严重智力障碍(ID)为特征的神经发育障碍,癫痫,喂养困难和新生儿低张力。
描述PURA综合征的临床谱并研究基因型-表型相关性。
在具有ID的个体中进行诊断或基于研究的外显子组或Sanger测序。我们系统地收集了新确定的PURA综合征个体的临床和突变数据,评估以前报告的个体的数据,并对照片进行计算分析。我们使用果蝇衍生的Pur-alpha同源物的晶体结构的3D计算机模拟模型,根据预测效果对突变进行分类。最后,我们通过分析复发突变和突变类别来探索基因型-表型相关性.
我们报告了32个个体中PURA(富含嘌呤的元件结合蛋白A)的突变,迄今为止描述的最大队列。临床数据评估,包括22个以前发表的案例,透露所有人都有中度至重度ID和新生儿发作症状,包括低张力(96%),呼吸系统问题(57%),喂养困难(77%),夸张的惊吓反应(44%),嗜睡(66%)和体温过低(35%)。癫痫(54%)和胃肠道(69%),经常观察到眼科(51%)和内分泌问题(42%)。面部照片的计算分析显示出微妙的面部畸形。通过将突变亚分组为功能类别,未鉴定出强的基因型-表型相关性。
我们通过鉴定另外32个个体来描绘PURA综合征的临床谱。通过靶向Sanger测序鉴定一个个体指向该综合征的临床可识别性。基因型-表型分析显示,突变类别与疾病严重程度之间没有显着相关性。
De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal
hypotonia.
To delineate the clinical spectrum of PURA syndrome and
study genotype-phenotype correlations.
Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.
We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including
hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.
We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.