Toshiyuki Yamamoto1, Taichi Imaizumi2, Keiko Yamamoto-Shimojima3, Yongping Lu4, Tomoe Yanagishita5, Shino Shimada6, Pin Fee Chong7, Ryutaro Kira7, Riyo Ueda8, Akihiko Ishiyama8, Eri Takeshita8, Ken Momosaki9, Shiro Ozasa9, Tomoyuki Akiyama10, Katsuhiro Kobayashi10, Hiroo Oomatsu11, Hikaru Kitahara11, Tokito Yamaguchi11, Katsumi Imai11, Hirokazu Kurahashi12, Akihisa Okumura12, Hirokazu Oguni6, Toshiyuki Seto13, Nobuhiko Okamoto14. 1. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Tokyo Women's Medical University Institute of Integrated Medical Sciences, Tokyo, Japan. Electronic address: yamamoto.toshiyuki@twmu.ac.jp. 2. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Department of Pediatrics, St. Mariannna University School of Medicine, Kawasaki, Japan. 3. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Tokyo Women's Medical University Institute of Integrated Medical Sciences, Tokyo, Japan. 4. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. 5. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan. 6. Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan. 7. Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan. 8. Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan. 9. Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 10. Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. 11. Department of Pediatrics, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Japan. 12. Department of Pediatrics, Aichi Medical University, Nagakute, Japan. 13. Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan. 14. Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.
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.
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.
Authors: Hilary C Martin; Eugene J Gardner; Kaitlin E Samocha; Joanna Kaplanis; Nadia Akawi; Alejandro Sifrim; Ruth Y Eberhardt; Ana Lisa Taylor Tavares; Matthew D C Neville; Mari E K Niemi; Giuseppe Gallone; Jeremy McRae; Caroline F Wright; David R FitzPatrick; Helen V Firth; Matthew E Hurles Journal: Nat Commun Date: 2021-01-27 Impact factor: 14.919