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Eur J Hum Genet. 2018 Jul;26(7):960-971. doi: 10.1038/s41431-018-0130-6. Epub 2018 Apr 23.

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience.

Author information

1
Laboratory of Rare and Autoinflammatory Genetic Diseases and CEREMAIA, Montpellier University Hospital, Montpellier, France.
2
Medical Information Department, Montpellier University Hospital, Montpellier, France.
3
General Pediatrics, Infectious Disease and Internal Medicine Department, AP-HP, Robert Debré Hospital, Paris, France.
4
Pediatric Hematology-Immunology and Rheumatology Department, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
5
Department of Dermatology, Saint-Eloi Hospital and Montpellier University Hospital, Montpellier, France.
6
Department of Dermatology, Hôpital d'Instruction des Armées Legouest, Metz, France.
7
Pediatric Neurology and National Reference Center for Neurogenetic Disorders, AP-HP, Trousseau Hospital, Paris, France.
8
GRC ConCer-LD, Sorbonne Universites, UPMC Universite, Paris, France.
9
Neuropediatrics, Gui de Chaulliac Hospital, Montpellier University Hospital, Montpellier, France.
10
Genetics and Immunopathology of Inflammatory Osteoarticular Diseases, INSERM UMR1183, Montpellier, France.
11
Department of Clinical Genetics, Montpellier University Hospital, Montpellier, France.
12
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
13
Division of Rheumatology, IRCCS Pediatrico Bambino Gesù Children's Hospital, Roma, Italy.
14
Department of Dermatology, Teaching Hospital Cochin, AP-HP, University Paris Descartes, Paris, France.
15
Internal Medicine, Archet-1 Hospital, Nice University Hospital, Nice, France.
16
Internal Medecine, Cochin Hospital, AP-HP, Paris Descartes University, Paris, France.
17
Pediatric Immunology-Hematology and Rheumatology Unit, Institut Imagine, AP-HP, Necker Enfants Malades Hospital, AP-HP, Paris, France.
18
Internal Medicine, CEREMAIA, Tenon Hospital, AP-HP, University of Pierre et Marie Curie, Paris, France.
19
Department of Paediatric Nephrology, Rheumatology and Dermatology, RAISE, Lyon University Hospital, Lyon, France.
20
Department of Paediatric Rheumatology, CEREMAIA, Bicêtre Hospital, AP-HP, University of Paris Sud, Le Kremlin-Bicêtre, France.
21
Department of Paediatrics, CEREMAIA, Versailles Hospital, Versailles, France.
22
Laboratory of Rare and Autoinflammatory Genetic Diseases and CEREMAIA, Montpellier University Hospital, Montpellier, France. guillaume.sarrabay@inserm.fr.
23
Genetics and Immunopathology of Inflammatory Osteoarticular Diseases, INSERM UMR1183, Montpellier, France. guillaume.sarrabay@inserm.fr.

Abstract

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.

Comment in

PMID:
29681619
PMCID:
PMC6018671
DOI:
10.1038/s41431-018-0130-6
[Indexed for MEDLINE]
Free PMC Article

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