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Clin Chem. 2020 Apr 1;66(4):525-536. doi: 10.1093/clinchem/hvaa024.

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

Author information

1
Laboratory of FMF, Amyloidosis and Rare Autoinflammatory Diseases, Heller Institute, Sheba Medical Center, Tel Hashomer, Israel.
2
UOC Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
3
National Amyloidosis Centre, UCL Medical School, London, UK.
4
National Human Genome Research Institute, Bethesda, MD.
5
Department of Immunology, Hospital Clínic, Barcelona, Spain.
6
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
7
Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
8
Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.
9
Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Giannina Gaslini, Genova.
10
Center of Medical Genetics and Primary Health Care, Yerevan, Armenia.
11
Department of Medicine, Division of Respirology, Neurology and Rheumatology, Kurume University School of Medicine, Kurume, Japan.
12
Department of Dermatology, Wakayama Medical University, Wakayama, Japan.
13
Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
14
ViennaLab Diagnostics, Vienna, Austria.
15
Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
16
Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan.
17
Department of Pediatrics, Hacettepe University, Ankara, Turkey.
18
European Molecular Genetics Quality Network (EMQN), Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK.
19
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
20
Stem Cells, Cellular Plasticity, Regenerative Medicine and Immunotherapies, INSERM, Montpellier, France.

Abstract

BACKGROUND:

Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.

METHODS:

The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.

RESULTS:

In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.

CONCLUSIONS:

These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.

KEYWORDS:

Next-Generation Sequencing (NGS); autoinflammatory diseases; genetic diagnosis; guidelines; variant analysis

PMID:
32176780
DOI:
10.1093/clinchem/hvaa024

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