Article Text
Abstract
Purpose To determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial NF2-related schwannomatosis.
Methods We conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria for NF2-related schwannomatosis. In addition to the current clinical screening techniques, targeted next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification analysis, we applied additional genetic screening techniques, including karyotype and RNA analysis. For characterisation of a complex structural variant, we also performed long-read sequencing analysis.
Results Additional genetic analysis resulted in increased sensitivity of detection of pathogenic variants from 87% to 95% in our second-generation NF2-related schwannomatosis cohort. A number of pathogenic variants identified through extended analysis had been previously observed after NGS analysis but had been overlooked or classified as variants of uncertain significance.
Conclusion Our study indicates there is added value in performing additional genetic analysis for detection of pathogenic variants that are difficult to identify with current clinical genetic screening methods. In particular, RNA analysis is valuable for accurate classification of non-canonical splicing variants. Karyotype analysis and whole genome sequencing analysis are of particular value for identification of large and/or complex structural variants, with additional advantages in the use of long-read sequencing techniques.
- Genetic Predisposition to Disease
- Genetic Research
- Diagnosis
Data availability statement
Data are available upon reasonable request.
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Data availability statement
Data are available upon reasonable request.
Footnotes
X @BurghelG
Presented at The long-read sequencing analysis of a complex structural rearrangement identified in an NF2-related schwannomatosis family was previously presented as an e-poster at the 55th European Society of Human Genetics (ESHG) Conference (doi: 10.1038/s41431-023-01346-4).
Contributors Conception and design: DGE. Supervision of data collection and analysis: DGE (clinical) and MJS (research). Analysis and interpretation of data: all authors. Drafting of the article: CP-B. Manuscript review and approval of the final submission: all authors. MJS is responsible for the overall content and acts as guarantor.
Funding The study received funding from USAMRAA CDMRP Neurofibromatosis Research Program Investigator-Initiated Research Award (W81XWH1910334).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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