@article {Iwama396, author = {Kazuhiro Iwama and Takeshi Mizuguchi and Eri Takeshita and Eiji Nakagawa and Tetsuya Okazaki and Yoshiko Nomura and Yoshitaka Iijima and Ichiro Kajiura and Kenji Sugai and Takashi Saito and Masayuki Sasaki and Kotaro Yuge and Tomoko Saikusa and Nobuhiko Okamoto and Satoru Takahashi and Masano Amamoto and Ichiro Tomita and Satoko Kumada and Yuki Anzai and Kyoko Hoshino and Aviva Fattal-Valevski and Naohide Shiroma and Masaharu Ohfu and Masaharu Moroto and Koichi Tanda and Tomoko Nakagawa and Takafumi Sakakibara and Shin Nabatame and Muneaki Matsuo and Akiko Yamamoto and Shoko Yukishita and Ken Inoue and Chikako Waga and Yoko Nakamura and Shoko Watanabe and Chihiro Ohba and Toru Sengoku and Atsushi Fujita and Satomi Mitsuhashi and Satoko Miyatake and Atsushi Takata and Noriko Miyake and Kazuhiro Ogata and Shuichi Ito and Hirotomo Saitsu and Toyojiro Matsuishi and Yu-ichi Goto and Naomichi Matsumoto}, title = {Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing}, volume = {56}, number = {6}, pages = {396--407}, year = {2019}, doi = {10.1136/jmedgenet-2018-105775}, publisher = {BMJ Publishing Group Ltd}, abstract = {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.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/56/6/396}, eprint = {https://jmg.bmj.com/content/56/6/396.full.pdf}, journal = {Journal of Medical Genetics} }