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Sadler, Katherine V; Bowers, Naomi L; Hartley, Claire; Smith, Philip T; Tobi, Simon; Wallace, Andrew J; King, Andrew; Lloyd, Simon K W; Rutherford, Scott; Pathmanaban, Omar N; Hammerbeck-Ward, Charlotte; Freeman, Simon; Stapleton, Emma; Taylor, Amy; Shaw, Adam; Halliday, Dorothy; Smith, Miriam Jane; Evans, D Gareth

Sporadic vestibular schwannoma: a molecular testing summary

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  • Medientyp: E-Artikel
  • Titel: Sporadic vestibular schwannoma: a molecular testing summary
  • Beteiligte: Sadler, Katherine V; Bowers, Naomi L; Hartley, Claire; Smith, Philip T; Tobi, Simon; Wallace, Andrew J; King, Andrew; Lloyd, Simon K W; Rutherford, Scott; Pathmanaban, Omar N; Hammerbeck-Ward, Charlotte; Freeman, Simon; Stapleton, Emma; Taylor, Amy; Shaw, Adam; Halliday, Dorothy; Smith, Miriam Jane; Evans, D Gareth
  • Erschienen: BMJ, 2021
  • Erschienen in: Journal of Medical Genetics
  • Sprache: Englisch
  • DOI: 10.1136/jmedgenet-2020-107022
  • ISSN: 0022-2593; 1468-6244
  • Schlagwörter: Genetics (clinical) ; Genetics
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Objectives</jats:title><jats:p>Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in <jats:italic>NF2</jats:italic> on blood samples for all patients, and tumour DNA samples when available. <jats:italic>LZTR1</jats:italic> and <jats:italic>SMARCB1</jats:italic> screening was also performed in patient subgroups.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline <jats:italic>NF2</jats:italic> variants were confirmed in 2% of patients. Pathogenic germline variants in <jats:italic>LZTR1</jats:italic> were found in 3% of all tested patients, with a higher rate of 5% in patients &lt;30 years. No pathogenic <jats:italic>SMARCB1</jats:italic> variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic <jats:italic>NF2</jats:italic> variants, including those with germline <jats:italic>LZTR1</jats:italic> pathogenic variants.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of <jats:italic>NF2</jats:italic> function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of <jats:italic>LZTR1</jats:italic>-associated VS tumourigenesis.</jats:p></jats:sec>