We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.

中文翻译：

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103个约旦家庭神经发育障碍的遗传基础。

我们从约旦招募了103个具有神经发育障碍（NDD）和遗传模式的家庭，这些遗传模式大多暗示常染色体隐性遗传。在每个家庭中，我们使用外显子组测序和包括拷贝数变异搜索在内的内部诊断变异解释管道，调查了至少一个受影响的个体。这种方法使我们确定了37个家庭中已建立的疾病基因中可能存在的分子缺陷。我们可以鉴定出25个致病性废话和11个错义变体，以及3个致病性拷贝数变异和1个重复扩增。值得注意的是，有11种疾病引起的变异是从头发生的。此外，我们优先考虑了智力障碍的两个姐妹在PUS3中的纯合移码变异。据我们所知，PUS3仅在最近才被假定为具有三个受影响兄弟姐妹的单个家庭中智力障碍的候选疾病基因。我们的发现提供了进一步的证据来证明PUS3功能丧失是智力障碍的原因。