Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders
Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders
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DOI：
10.1016/j.braindev.2019.05.007
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发表时间：
2019-10-01
影响因子：
1.7
通讯作者：
Okamoto, Nobuhiko
中科院分区：
文献类型：
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作者：
Yamamoto, Toshiyuki;Imaizumi, Taichi;Okamoto, Nobuhiko
背景资料：近年来，通过高通量基因组分析，许多与神经发育障碍相关的基因已被鉴定，然而，对神经发育障碍的机制仍有待建立全面的了解。为了进一步了解这些潜在的机制，我们对未确诊的神经发育障碍患者进行了全面的基因组分析。使用下一代测序和靶向面板对总共133名日本患者进行基因组分析（男性/女性，81/52）既往未诊断的神经发育障碍，包括发育迟缓（DD）、智力残疾（ID），自闭症谱系障碍（ASD）和癫痫。结果：39例患者（29.3%）表现出致病性或可能致病的单基因变异或染色体畸变的结果，使用eXome隐马尔可夫模型（XHMM）的基因组拷贝数进行了分析。其中，20例患者在这里介绍。在18个基因中发现致病或可能致病的变异，包括ACTGI、CACNA 1A、CHD 2、CDKL 5、DNMT 3A、EHMT 1、GABRB 3、GABRG 2、GRIN 2B、KCNQ 3、KDM 5C、MED 13 L、SCN 2A、SHANKS、SMARCA 2、STXBP 1、SYNGAP 1和TBL 1XR 1。结论：本研究的诊断率为29.3%，与国外报道的诊断率基本一致。因此，我们认为，在日本未确诊的神经发育障碍患者的基因组背景没有差异。虽然大多数患者具有新生变异，但其中一名患者显示X连锁遗传模式。由于X连锁隐性遗传病在家族中具有反复发生的可能性，因此综合性的分子诊断对于遗传咨询非常重要。(C)2019日本儿童神经病学学会。Elsevier B. V.出版，保留所有权利。
Background: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders.Methods: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM).Results: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTGI, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANKS, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1.Conclusion: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling. (C) 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.