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Original research
Improved sensitivity for detection of pathogenic variants in familial NF2-related schwannomatosis
  1. Cristina Perez-Becerril1,2,
  2. George J Burghel1,2,
  3. Claire Hartley1,
  4. Charles F Rowlands3,
  5. D Gareth Evans1,2,
  6. Miriam J Smith1,2
  1. 1 Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK
  2. 2 Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK
  3. 3 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  1. Correspondence to Dr Miriam J Smith, Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester, Manchester, M13 9WL, UK; miriam.smith{at}


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.

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  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.