New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID).
J Med Genet
; 55(8): 530-537, 2018 08.
Article
em En
| MEDLINE
| ID: mdl-29599418
ABSTRACT
BACKGROUND:
Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.OBJECTIVES:
This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes MEFV, TNFRSF1A, NLRP3 and MVK.METHODS:
We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds.RESULTS:
Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene.CONCLUSION:
Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http//github.com/molgenis/molgenis; the specific HRF configuration is available at http//molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https//fmf.igh.cnrs.fr/ISSAID/infevers/.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Variação Genética
/
Predisposição Genética para Doença
/
Doenças Hereditárias Autoinflamatórias
/
Estudos de Associação Genética
/
Fluxo de Trabalho
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Holanda