In:
Journal of Medical Genetics, BMJ, Vol. 56, No. 6 ( 2019-06), p. 396-407
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmedgenet-2018-105775
Language:
English
Publisher:
BMJ
Publication Date:
2019
detail.hit.zdb_id:
2009590-9
SSG:
12
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