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. 2019 Jun;56(6):396-407.
doi: 10.1136/jmedgenet-2018-105775. Epub 2019 Mar 6.

Genetic Landscape of Rett Syndrome-Like Phenotypes Revealed by Whole Exome Sequencing

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Genetic Landscape of Rett Syndrome-Like Phenotypes Revealed by Whole Exome Sequencing

Kazuhiro Iwama et al. J Med Genet. .

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.

Keywords: mast3; ncor2; rett syndrome; usp8; whole exome sequencing.

Conflict of interest statement

Competing interests: None declared.

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