Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders

Toshiyuki Yamamoto, Taichi Imaizumi, K. Yamamoto-Shimojima, Yongping Lu, T. Yanagishita, S. Shimada, Pin Fee Chong, Ryutaro Kira, Riyo Ueda, Akihiko Ishiyama, Eri Takeshita, Ken Momosaki, S. Ozasa, Tomoyuki Akiyama, Katsuhiro Kobayashi, H. Oomatsu, Hikaru Kitahara, Tokito Yamaguchi, Katsumi Imai, Hirokazu KurahashiAkihisa Okumura, Hirokazu Oguni, Toshiyuki Seto, Nobuhiko Okamoto

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


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 ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, 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.

Original languageEnglish
Pages (from-to)776-782
Number of pages7
JournalBrain and Development
Issue number9
Publication statusPublished - Oct 2019


  • Dysmorphism
  • Genomic copy number variations
  • Single nucleotide variants
  • X-linked recessive

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Clinical Neurology


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