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Original article
Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing
  1. Kazuhiro Iwama1,2,
  2. Takeshi Mizuguchi1,
  3. Eri Takeshita3,4,
  4. Eiji Nakagawa3,
  5. Tetsuya Okazaki5,
  6. Yoshiko Nomura6,
  7. Yoshitaka Iijima7,
  8. Ichiro Kajiura7,
  9. Kenji Sugai3,
  10. Takashi Saito3,
  11. Masayuki Sasaki3,
  12. Kotaro Yuge8,
  13. Tomoko Saikusa8,
  14. Nobuhiko Okamoto9,
  15. Satoru Takahashi10,
  16. Masano Amamoto11,
  17. Ichiro Tomita11,
  18. Satoko Kumada12,
  19. Yuki Anzai13,
  20. Kyoko Hoshino13,
  21. Aviva Fattal-Valevski14,
  22. Naohide Shiroma15,
  23. Masaharu Ohfu16,
  24. Masaharu Moroto17,18,
  25. Koichi Tanda17,
  26. Tomoko Nakagawa19,
  27. Takafumi Sakakibara19,
  28. Shin Nabatame20,
  29. Muneaki Matsuo21,
  30. Akiko Yamamoto22,
  31. Shoko Yukishita6,
  32. Ken Inoue4,
  33. Chikako Waga4,
  34. Yoko Nakamura4,
  35. Shoko Watanabe23,
  36. Chihiro Ohba1,
  37. Toru Sengoku24,
  38. Atsushi Fujita1,
  39. Satomi Mitsuhashi1,
  40. Satoko Miyatake1,25,
  41. Atsushi Takata1,
  42. Noriko Miyake1,
  43. Kazuhiro Ogata24,
  44. Shuichi Ito2,25,
  45. Hirotomo Saitsu26,
  46. Toyojiro Matsuishi27,
  47. Yu-ichi Goto4,23,
  48. Naomichi Matsumoto1
  1. 1 Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
  2. 2 Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
  3. 3 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
  4. 4 Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
  5. 5 Department of Pediatrics, Nippon Medical School Tama-Nagayama Hospital, Tokyo, Japan
  6. 6 Yoshiko Nomura Neurological Clinic for Children, Tokyo, Japan
  7. 7 Division of Pediatrics, Osaka Developmental Rehabilitation Center, Osaka, Japan
  8. 8 Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan
  9. 9 Deparment of Medical Genetics, Osaka Women’s and Children’s Hospital, Osaka, Japan
  10. 10 Department of Pediatrics, Asahikawa Medical University, Hokkaido, Japan
  11. 11 Department of Pediatrics, Kitakyushu Municipal Yahata Hospital, Fukuoka, Japan
  12. 12 Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
  13. 13 Segawa Memorial Neurological Clinic for Children, Tokyo, Japan
  14. 14 Pediatric Neurology Unit, Dana-Dwek Children’s Hospital, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  15. 15 Neurodevelopment Clinic Prop, Okinawa, Japan
  16. 16 Division of Child Neurology, Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center, Okinawa, Japan
  17. 17 Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
  18. 18 Kyoto Prefectural Chutan-Nishi Public Health Center, Kyoto, Japan
  19. 19 Department of Pediatrics, Nara Medical University, Nara, Japan
  20. 20 Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan
  21. 21 Department of Pediatrics, Saga University, Faculty of Medicine, Saga, Japan
  22. 22 Division of Pediatrics, Tokyo Metropolitan Tobu Medical Center for Persons with Developmental and Multiple Disabilities, Tokyo, Japan
  23. 23 Department of Genome Medicine Development, Medical Genome Center (MGC), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
  24. 24 Department of Biochemistry, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
  25. 25 Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan
  26. 26 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
  27. 27 Research Center for Children and Research Center for Rett Syndrome, St. Mary’s Hospital, Fukuoka, Japan
  1. Correspondence to Professor Naomichi Matsumoto, Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; naomat{at}


Background Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).

Methods We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.

Results Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2).

Conclusions Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

  • rett syndrome
  • whole exome sequencing
  • mast3
  • usp8
  • ncor2

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  • Contributors KaI and NaM designed the analyses, collected and interpreted the data, and wrote the manuscript. KaI and AT performed the bioinformatic analysis. ToSen and KO performed structural analyses. AF performed targeted amplicon sequencing. ET, SY, KeI, CW, YNa, SW and YG performed the prescreening for patients before enrolling patients to this study. ET, EN, TO, YI, YNo, IK, KS, TaSai, MS, KY, ToSai, NO, ST, MA, IT, SK, YA, KH, AFV, NS, MO, MaM, KT, TN, TaSak, SN, MuM, AY and ToM performed clinical evaluation of patients. TaM, CO, SMit, SMiy, AT, NoM, SI and HS interpreted the results, and critically reviewed the manuscript. All authors reviewed and approved the manuscript.

  • Funding This work was supported by Japan Agency for Medical Research and Development (AMED) under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348 and JP18kk020500; by JSPS KAKENHI under grant numbers JP17H01539, JP16H05357, JP17K10080 and JP17K15630; the Ministry of Health, Labour and Welfare and Takeda Science Foundation.

  • Competing interests None declared.

  • Ethics approval This study was approved by the Institutional Review Board of Yokohama City University of Medicine.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Patient consent for publication Obtained.