Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders

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

Research output: Contribution to journalArticle

Abstract

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
JournalBrain and Development
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Genes
Exome
Inheritance Patterns
X-Linked Genes
Genetic Counseling
Neurodevelopmental Disorders
Chromosome Aberrations
Intellectual Disability
Epilepsy
Autism Spectrum Disorder

Keywords

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

ASJC Scopus subject areas

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

Cite this

Yamamoto, T., Imaizumi, T., Yamamoto-Shimojima, K., Lu, Y., Yanagishita, T., Shimada, S., ... Okamoto, N. (2019). Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. Brain and Development. https://doi.org/10.1016/j.braindev.2019.05.007

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. / Yamamoto, Toshiyuki; Imaizumi, Taichi; Yamamoto-Shimojima, Keiko; Lu, Yongping; Yanagishita, Tomoe; Shimada, Shino; Chong, Pin Fee; Kira, Ryutaro; Ueda, Riyo; Ishiyama, Akihiko; Takeshita, Eri; Momosaki, Ken; Ozasa, Shiro; Akiyama, Tomoyuki; Kobayashi, Katsuhiro; Oomatsu, Hiroo; Kitahara, Hikaru; Yamaguchi, Tokito; Imai, Katsumi; Kurahashi, Hirokazu; Okumura, Akihisa; Oguni, Hirokazu; Seto, Toshiyuki; Okamoto, Nobuhiko.

In: Brain and Development, 01.01.2019.

Research output: Contribution to journalArticle

Yamamoto, T, Imaizumi, T, Yamamoto-Shimojima, K, Lu, Y, Yanagishita, T, Shimada, S, Chong, PF, Kira, R, Ueda, R, Ishiyama, A, Takeshita, E, Momosaki, K, Ozasa, S, Akiyama, T, Kobayashi, K, Oomatsu, H, Kitahara, H, Yamaguchi, T, Imai, K, Kurahashi, H, Okumura, A, Oguni, H, Seto, T & Okamoto, N 2019, 'Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders', Brain and Development. https://doi.org/10.1016/j.braindev.2019.05.007
Yamamoto, Toshiyuki ; Imaizumi, Taichi ; Yamamoto-Shimojima, Keiko ; Lu, Yongping ; Yanagishita, Tomoe ; Shimada, Shino ; Chong, Pin Fee ; Kira, Ryutaro ; Ueda, Riyo ; Ishiyama, Akihiko ; Takeshita, Eri ; Momosaki, Ken ; Ozasa, Shiro ; Akiyama, Tomoyuki ; Kobayashi, Katsuhiro ; Oomatsu, Hiroo ; Kitahara, Hikaru ; Yamaguchi, Tokito ; Imai, Katsumi ; Kurahashi, Hirokazu ; Okumura, Akihisa ; Oguni, Hirokazu ; Seto, Toshiyuki ; Okamoto, Nobuhiko. / Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. In: Brain and Development. 2019.
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abstract = "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.",
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T1 - Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders

AU - Yamamoto, Toshiyuki

AU - Imaizumi, Taichi

AU - Yamamoto-Shimojima, Keiko

AU - Lu, Yongping

AU - Yanagishita, Tomoe

AU - Shimada, Shino

AU - Chong, Pin Fee

AU - Kira, Ryutaro

AU - Ueda, Riyo

AU - Ishiyama, Akihiko

AU - Takeshita, Eri

AU - Momosaki, Ken

AU - Ozasa, Shiro

AU - Akiyama, Tomoyuki

AU - Kobayashi, Katsuhiro

AU - Oomatsu, Hiroo

AU - Kitahara, Hikaru

AU - Yamaguchi, Tokito

AU - Imai, Katsumi

AU - Kurahashi, Hirokazu

AU - Okumura, Akihisa

AU - Oguni, Hirokazu

AU - Seto, Toshiyuki

AU - Okamoto, Nobuhiko

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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KW - Genomic copy number variations

KW - Single nucleotide variants

KW - X-linked recessive

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