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 language | English |
|---|---|
| Journal | Brain and Development |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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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
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 journal › Article
}
TY - JOUR
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.
KW - Dysmorphism
KW - Genomic copy number variations
KW - Single nucleotide variants
KW - X-linked recessive
UR - http://www.scopus.com/inward/record.url?scp=85066402522&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066402522&partnerID=8YFLogxK
U2 - 10.1016/j.braindev.2019.05.007
DO - 10.1016/j.braindev.2019.05.007
M3 - Article
C2 - 31171384
AN - SCOPUS:85066402522
JO - Brain and Development
JF - Brain and Development
SN - 0387-7604
ER -