BACKGROUND Rare denovo variants represent a significant cause of neurodevelopmental delay and intellectual disability (ID). METHODS Exome sequencing was performed on 4351 patients with global developmental delay, seizures, microcephaly, macrocephaly, motor delay, delayed speech and language development, or ID according to Human Phenotype Ontology (HPO) terms. All patients had previously undergone whole exome sequencing as part of diagnostic genetic testing with a focus on variants in genes implicated in neurodevelopmental disorders up to January 2017. This resulted in a genetic diagnosis in 1336 of the patients. In this study, we specifically searched for variants in 14 recently implicated novel neurodevelopmental disorder (NDD) genes. RESULTS We identified 65 rare, protein-changing variants in 11 of these 14 novel candidate genes. Fourteen variants in CDK13, CHD4, KCNQ3, KMT5B, TCF20, and ZBTB18 were scored pathogenic or likely pathogenic. Of note, two of these patients had a previously identified cause of their disease, and thus, multiple molecular diagnoses were made including pathogenic/likely pathogenic variants in FOXG1 and CDK13 or in TMEM237 and KMT5B. CONCLUSIONS Looking for pathogenic variants in newly identified NDD genes enabled us to provide a molecular diagnosis to 14 patients and their close relatives and caregivers. This underlines the relevance of re-evaluation of existing exome data on a regular basis to improve the diagnostic yield and serve the needs of our patients.

中文翻译：

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神经发育障碍的新型致病变异和多种分子诊断。

背景技术罕见的denovo变体代表神经发育延迟和智力障碍（ID）的重要原因。方法根据人类表型本体论（HPO）术语，对4351例具有整体发育迟缓，癫痫发作，小头畸形，大头畸形，运动迟缓，语言和语言发育迟缓或ID的患者进行了外显子测序。之前，所有患者先前均已进行了完整的外显子组测序，作为诊断性基因测试的一部分，重点是截至2017年1月的神经发育障碍相关基因的变异。这导致对1336名患者进行了基因诊断。在这项研究中，我们专门搜索了14个最近涉及的新型神经发育障碍（NDD）基因的变体。结果我们在这14个新的候选基因中的11个中鉴定出65个稀有的，可改变蛋白质的变体。将CDK13，CHD4，KCNQ3，KMT5B，TCF20和ZBTB18中的14个变体评分为致病性或可能致病性。值得注意的是，这些患者中有两个以前已经确定了其病因，因此进行了多种分子诊断，包括FOXG1和CDK13或TMEM237和KMT5B中的致病性/可能致病性变异。结论在新近鉴定的NDD基因中寻找致病变异，使我们能够为14例患者及其近亲和照顾者提供分子诊断。这强调了定期重新评估现有外显子组数据的相关性，以提高诊断率并满足我们患者的需求。进行了多种分子诊断，包括FOXG1和CDK13或TMEM237和KMT5B中的致病/可能致病变体。结论在新近鉴定的NDD基因中寻找致病变异，使我们能够为14例患者及其近亲和护理人员提供分子诊断。这强调了定期重新评估现有外显子组数据的相关性，以提高诊断率并满足我们患者的需求。进行了多种分子诊断，包括FOXG1和CDK13或TMEM237和KMT5B中的致病/可能致病变体。结论在新近鉴定的NDD基因中寻找致病变异，使我们能够为14例患者及其近亲和照顾者提供分子诊断。这强调了定期重新评估现有外显子组数据的相关性，以提高诊断率并满足我们患者的需求。