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Improved sensitivity for detection of pathogenic variants in familial NF2-related schwannomatosis.
Perez-Becerril, Cristina; Burghel, George J; Hartley, Claire; Rowlands, Charles F; Evans, D Gareth; Smith, Miriam J.
Affiliation
  • Perez-Becerril C; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
  • Burghel GJ; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK.
  • Hartley C; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
  • Rowlands CF; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK.
  • Evans DG; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
  • Smith MJ; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
J Med Genet ; 61(5): 452-458, 2024 Apr 19.
Article in En | MEDLINE | ID: mdl-38302265
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.
Subject(s)
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Skin Neoplasms / Neurofibromatoses / Neurilemmoma Type of study: Diagnostic_studies / Prognostic_studies Limits: Humans Language: En Journal: J Med Genet / J. med. genet. (Online) / Journal of medical genetics (Online) Year: 2024 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Skin Neoplasms / Neurofibromatoses / Neurilemmoma Type of study: Diagnostic_studies / Prognostic_studies Limits: Humans Language: En Journal: J Med Genet / J. med. genet. (Online) / Journal of medical genetics (Online) Year: 2024 Type: Article