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
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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.
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