Targeted Next-Generation Sequencing of Korean Patients With Developmental Delay and/or Intellectual Disability
Targeted Next-Generation Sequencing of Korean Patients With Developmental Delay and/or Intellectual Disability
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DOI：
10.3389/fped.2018.00391
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发表时间：
2018-12-17
影响因子：
2.6
通讯作者：
Lee, In Goo
中科院分区：
文献类型：
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作者：
Han, Ji Yoon;Jang, Ja Hyun;Lee, In Goo
背景：发育迟缓(DD)和/或智力残疾(ID)的鉴别诊断具有挑战性，因为DD/ID患者通常合并先天性畸形、自闭症谱系障碍和/或癫痫障碍，因此具有多样性的表型表现。目的：探讨靶向下一代测序(NGS)在35例不明原因DD/ID韩国患者中的临床应用价值。方法：采用TruSight One Panel对35例不明原因DD/ID患者进行靶向下一代测序(NGS)分析。采用Sanger测序确定候选变异，并将候选变异的遗传模式定义为家系分离试验。结果：35例DD和/或ID患者中，10例具有潜在的遗传病因，携带ZDHHC9的X连锁隐性遗传或SMARCB1、CHD8、LAMA5、NSD1、PAX6、CACNA1H、MBD5、Foxp1或KCNK18突变的常染色体显性遗传。本研究未发现常染色体隐性遗传突变。结果表明，靶向NGS对DD/ID的诊断准确率为29%(10/35)，主要涉及先证者可能存在的从头突变。在除LAMA5外的9例患者中发现了7个可能是新生突变，1个是父系遗传，1个是母系遗传突变，这些突变被认为是已知的DD和/或ID基因的遗传机制。在OMIM数据库中有相似DD/ID表型的患者中，检测到9个致病基因的突变，为遗传证据作为DD和/或ID的原因提供了支持。结论：通过表型优先的方法通过单例分析靶向NGS能够解释35例DD/ID病例中的10例。然而，可能的遗传原因的挖掘可能是从头开始的，而与DD/ID相关的基因中的X连锁致病变异需要进一步的遗传分析。
Background: Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID.Objective: The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID.Methods: Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing.Results: Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of ZDHHC9 or autosomal dominant inheritance of SMARCB1 , CHD8, LAMA5, NSD1 , PAX6, CACNA1H, MBD5, FOXP1 , or KCNK18 mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be de novo mutation present in the proband only. A total of seven may be de novo mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except LAMA5. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID.Conclusion: Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be de novo, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.