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Genetic Approach to the Diagnosis of Autoinflammatory Diseases

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Textbook of Autoinflammation

Abstract

Over the past 20 years, almost 30 new genes associated with autoinflammatory disorders have been identified. The genetic diagnosis is based on the identification of clearly pathogenic mutations, even in atypical cases (i.e. patients not meeting recognized clinical criteria). Therefore, genetic testing should be preferably ordered by healthcare providers who are familiar with the spectrum of clinical presentation of autoinflammatory diseases.

The constellation of clinical findings will guide the choice of genetic testing. The prerequisites that are usually asked before requesting a genetic test for suspected autoinflammatory disease are: evidence for systemic inflammation, suspicion of a monogenic trait i.e. for example early-onset disease or familial inheritance, and existence of a plausible candidate causal gene.

Sequencing approaches remain the gold-standard techniques. Sanger sequencing is a rapid, inexpensive method to test for mutations in a single gene in a single patient. However, its performance is low (10–20%) when examined in all patients tested for autoinflammatory disorders, including those who did not fulfil the criteria discussed above. The indications for Sanger sequencing should be restricted to prevalent mutations and/or mutational hot spots in a gene (e.g. extracellular domain of TNFRSF1A responsible for tumor necrosis factor receptor-associated periodic syndrome—TRAPS), or to patients with a complementary biochemical diagnosis (e.g. mevalonate kinase deficiency—MKD, deficiency of adenosine deaminase 2—DADA2).

If Sanger method is not confirmatory, large scale next generation sequencing (NGS) approaches should be contemplated. NGS allows investigations of multiple genes in multiple patients at a time. Targeted NGS sequencing of gene panels has become more time- and cost-effective and is commonly used today for phenotypically undifferentiated autoinflammatory diseases, genes known to harbour mosaic mutations (e.g. NLRP3) and oligogenism (e.g. proteasomopathies). New concepts regarding modes of inheritance and interpretation of variant pathogenicity will require a systematic review and update of genetic diagnostic strategies and new guidance on standardization and reporting of genetic tests.

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Abbreviations

ADA2:

Adenosine deaminase 2

APLAID:

Autoinflammation, PLCG2-associated antibody deficiency, and immune dysregulation

CAPS:

Cryopyrin-associated periodic syndrome

CRP:

C reactive protein

DADA2:

Deficiency of adenosine deaminase 2

DSAP:

Disseminated superficial actinic porokeratosis

ESR:

Erythrocyte sedimentation rate

FMF:

Familial Mediterranean fever

ISSAID:

International Society for Systemic Autoinflammatory Diseases

LUBAC:

linear ubiquitin chain assembly complex

MAF:

Minor allele frequency

MEFV :

Mediterranean fever (gene)

MKD:

Mevalonate kinase deficiency

NGS:

Next generation sequencing

NLRP3:

NLR pyrin domain containing protein 3

NOMID/CINCA:

Neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome

PAAND:

Pyrin-associated autoinflammation with neutrophilic dermatosis

PLAID:

PLCG2-associated antibody deficiency and immune dysregulation

PRAAS:

Proteasome-associated autoinflammatory syndromes

SAA:

Serum amyloid A

SAVI:

STING-associated vasculopathy with onset in infancy

SIFD:

Sideroblastic anemia with immunodeficiency, fevers and developmental delay

SNP:

Single nucleotide polymorphism

TRAPS:

Tumor necrosis factor receptor-associated periodic syndrome

VUS/VOUS:

Variant of unclear significance

WES:

Whole exome sequencing

WGS:

Whole genome sequencing

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Authors and Affiliations

  1. Stem Cells, Cellular Plasticity, Regenerative Medicine and Immunotherapies, INSERM, University Montpellier, Montpellier, France

    Isabelle Touitou

  2. Department of Medical Genetics, Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France

    Isabelle Touitou

  3. National Human Genome Research Institute, Bethesda, MD, USA

    Ivona Aksentijevich

Authors
  1. Isabelle Touitou
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  2. Ivona Aksentijevich
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Correspondence to Isabelle Touitou .

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Editors and Affiliations

  1. Pediatric Rheumatology Unit, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel

    Philip J. Hashkes

  2. Department Paediatrics, Division of Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

  3. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

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Touitou, I., Aksentijevich, I. (2019). Genetic Approach to the Diagnosis of Autoinflammatory Diseases. In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_12

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  • DOI: https://doi.org/10.1007/978-3-319-98605-0_12

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