Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing. Issue 6 (6th March 2019)

• Record Type: Journal Article
• Authors: Iwama, Kazuhiro; Mizuguchi, Takeshi; Takeshita, Eri; Nakagawa, Eiji; Okazaki, Tetsuya; Nomura, Yoshiko; Iijima, Yoshitaka; Kajiura, Ichiro; Sugai, Kenji; Saito, Takashi; Sasaki, Masayuki; Yuge, Kotaro; Saikusa, Tomoko; Okamoto, Nobuhiko; Takahashi, Satoru; Amamoto, Masano; Tomita, Ichiro; Kumada, Satoko; Anzai, Yuki; Hoshino, Kyoko; Fattal-Valevski, Aviva; Shiroma, Naohide; Ohfu, Masaharu; Moroto, Masaharu; Tanda, Koichi; Nakagawa, Tomoko; Sakakibara, Takafumi; Nabatame, Shin; Matsuo, Muneaki; Yamamoto, Akiko; Yukishita, Shoko; Inoue, Ken; Waga, Chikako; Nakamura, Yoko; Watanabe, Shoko; Ohba, Chihiro; Sengoku, Toru; Fujita, Atsushi; Mitsuhashi, Satomi; Miyatake, Satoko; Takata, Atsushi; Miyake, Noriko; Ogata, Kazuhiro; Ito, Shuichi; Saitsu, Hirotomo; Matsuishi, Toyojiro; Goto, Yu-ichi; Matsumoto, Naomichi;
• Is Part Of: Journal of medical genetics. Volume 56:Issue 6(2019)
• Page Start: 396
• Page End: 407
• Publication Date: 2019-03-06
• Subjects: rett syndrome -- whole exome sequencing -- mast3 -- usp8 -- ncor2; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2018-105775
• Languages: English
• ISSNs: 1468-6244

Abstract

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.