Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability.
Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability.
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DOI：
10.1136/jmedgenet-2014-102798
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发表时间：
2014-12
影响因子：
4
通讯作者：
Baralle D
中科院分区：
文献类型：
--
作者：
Hunt D;Leventer RJ;Simons C;Taft R;Swoboda KJ;Gawne-Cain M;DDD study;Magee AC;Turnpenny PD;Baralle D
新生突变正在成为神经认知障碍的一个重要原因，而病例-父母三人组的全外显子组测序是检测它们的一种强有力的方法。在这里，我们报告的结果在四个这样的三重奏。解密发育障碍研究正在使用家庭三人组的全外显子组测序来调查患有严重的，散发的，未确诊的发育迟缓的儿童。我们的三名患者是从第一批1133名儿童中确定的，他们通过这项大规模研究进行了调查。病例4是一个表型孤立的病例，被招募到一个未诊断的罕见疾病测序研究中。在4例受试者中发现了改变蛋白质的PURA新生突变。它们包括两个不同的移码，一个框内缺失和一个错义突变。PURA编码Pur-α，这是一种高度保守的多功能蛋白，在动物模型的正常出生后脑发育中起重要作用。该基因的从头杂合突变的相关人类表型是可变的，但中度至重度神经发育迟缓和学习障碍是所有人共同的。新生儿肌张力减退、早期喂养困难和癫痫发作或“痉挛样”运动也很常见。此外，它被怀疑，垂体前叶失调可能在这种疾病的频谱。患者之间的精神发育结局似乎是可变的，我们提出了一个可能的基因型-表型相关性，Pur重复序列III的破坏导致更严重的表型。这些研究结果提供了明确的证据表明，PURA在引起人类神经发育迟缓、学习障碍、新生儿张力减退、喂养困难、异常运动和癫痫等可变综合征中的作用，并有助于阐明PURA在先前描述的5q31.3微缺失表型中的作用。
De novo mutations are emerging as an important cause of neurocognitive impairment, and whole exome sequencing of case-parent trios is a powerful way of detecting them. Here, we report the findings in four such trios. The Deciphering Developmental Disorders study is using whole exome sequencing in family trios to investigate children with severe, sporadic, undiagnosed developmental delay. Three of our patients were ascertained from the first 1133 children to have been investigated through this large-scale study. Case 4 was a phenotypically isolated case recruited into an undiagnosed rare disorders sequencing study. Protein-altering de novo mutations in PURA were identified in four subjects. They include two different frameshifts, one inframe deletion and one missense mutation. PURA encodes Pur-α, a highly conserved multifunctional protein that has an important role in normal postnatal brain development in animal models. The associated human phenotype of de novo heterozygous mutations in this gene is variable, but moderate to severe neurodevelopmental delay and learning disability are common to all. Neonatal hypotonia, early feeding difficulties and seizures, or ‘seizure-like’ movements, were also common. Additionally, it is suspected that anterior pituitary dysregulation may be within the spectrum of this disorder. Psychomotor developmental outcomes appear variable between patients, and we propose a possible genotype–phenotype correlation, with disruption of Pur repeat III resulting in a more severe phenotype. These findings provide definitive evidence for the role of PURA in causing a variable syndrome of neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements and epilepsy in humans, and help clarify the role of PURA in the previously described 5q31.3 microdeletion phenotype.
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