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Genotype-phenotype correlations
Original research
Revisiting the UK Genetic Severity Score for NF2: a proposal for the addition of a functional genetic component
  1. Núria Catasús1,
  2. Belen Garcia1,2,
  3. Iván Galván-Femenía3,
  4. Adrià Plana4,
  5. Alejandro Negro1,2,
  6. Inma Rosas1,5,
  7. Andrea Ros1,2,
  8. Emilio Amilibia6,
  9. Juan Luis Becerra7,
  10. Cristina Hostalot8,
  11. Francesc Rocaribas6,
  12. Isabel Bielsa4,
  13. Conxi Lazaro Garcia9,
  14. Rafael de Cid3,
  15. Eduard Serra10,
  16. Ignacio Blanco1,2,
  17. Elisabeth Castellanos1,5
  18. On behalf of NF2 Spanish National Reference Centre HUGTP-ICO-IGTP
  1. 1 Clinical Genomics Research Unit, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP-PMPPC), Badalona, Spain
  2. 2 Genetic Counseling Unit, Clinical Genetics Service, Northern Metropolitan Clinical Laboratory, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  3. 3 Genomes for Life—GCAT lab Group, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain
  4. 4 Dermatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  5. 5 Clinical Genomics Unit, Clinical Genetics Service, Northern Metropolitan Clinical Laboratory, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  6. 6 Otorhinolaryngology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  7. 7 Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  8. 8 Neurosurgery, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  9. 9 Hereditary Cancer Program, ICO-IDIBELL-CIBERONC, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
  10. 10 Hereditary Cancer Group, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP-PMPPC), Badalona, Spain
  1. Correspondence to Dr Elisabeth Castellanos, Clinical Genomics Research Unit, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP-PMPPC), Badalona, Catalunya, Spain; ecastellanos{at}igtp.cat

Abstract

Background Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by the development of multiple schwannomas, especially on vestibular nerves, and meningiomas. The UK NF2 Genetic Severity Score (GSS) is useful to predict the progression of the disease from germline NF2 pathogenic variants, which allows the clinical follow-up and the genetic counselling offered to affected families to be optimised.

Methods 52 Spanish patients were classified using the GSS, and patients’ clinical severity was measured and compared between GSS groups. The GSS was reviewed with the addition of phenotype quantification, genetic variant classification and functional assays of Merlin and its downstream pathways. Principal component analysis and regression models were used to evaluate the differences between severity and the effect of NF2 germline variants.

Results The GSS was validated in the Spanish NF2 cohort. However, for 25% of mosaic patients and patients harbouring variants associated with mild and moderate phenotypes, it did not perform as well for predicting clinical outcomes as it did for pathogenic variants associated with severe phenotypes. We studied the possibility of modifying the mutation classification in the GSS by adding the impact of pathogenic variants on the function of Merlin in 27 cases. This revision helped to reduce variability within NF2 mutation classes and moderately enhanced the correlation between patient phenotype and the different prognosis parameters analysed (R2=0.38 vs R2=0.32, p>0001).

Conclusions We validated the UK NF2 GSS in a Spanish NF2 cohort, despite the significant phenotypic variability identified within it. The revision of the GSS, named Functional Genetic Severity Score, could add value for the classification of mosaic patients and patients showing mild and moderate phenotypes once it has been validated in other cohorts.

  • genetics
  • Genetic Association Studies
  • genetic predisposition to disease
  • congenital
  • hereditary
  • neonatal diseases and abnormalities

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data supporting the findings of this study are included in the article or supplementary information. Extra data are available on request from the corresponding author.

https://doi.org/10.1136/jmedgenet-2020-107548

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. All data supporting the findings of this study are included in the article or supplementary information. Extra data are available on request from the corresponding author.

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    Footnotes

    • Twitter @-, @elishabeba82

    • IB and EC contributed equally.

    • Contributors EC and IBl designed the study and wrote the manuscript that was revised, corrected, and improved by all authors. NC and BG performed most of the experimental work and analyzed the data. NC generated the figures for the paper and contributed in writing the manuscript. IG-F and RdC performed bioinformatic analysis. IR and AN performed genetic analysis and experimental work. AR, AP, EA, JLB, CH, FR, IBi contributed with clinical data collection. CL and ES provided scientific input. All authors approved the final version of the manuscript.

    • Funding This work has been supported by The Spanish NF lay association through Neurofibromatosis project foundation, Spanish federation of rare diseases (feder); the IGTP-PMPPC and the Government of Catalonia (2017 SGR 496).

    • 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.