A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience
Mélanie Rama
(1, 2)
,
Claire Duflos
(2)
,
Isabelle Melki
(3, 4)
,
Didier Bessis
(5, 6)
,
Axelle Bonhomme
(7)
,
Hélène Martin
(7)
,
Diane Doummar
(8)
,
Stephanie Valence
(8)
,
Diana Rodriguez
(8)
,
Emilie Carme
(9)
,
David Geneviève
(1, 10, 2)
,
Ketil Heimdal
(11)
,
Antonella Insalaco
(12)
,
Nathalie Franck
(13, 14)
,
Viviane Queyrel-Moranne
(15)
,
Nathalie Tieulie
(15)
,
Jonathan London
(16)
,
Florence Uettwiller
(4)
,
Sophie Georgin-Lavialle
(17, 18)
,
Alexandre Belot
(19)
,
Isabelle Kone-Paut
(20)
,
Véronique Hentgen
(21)
,
Guilaine Boursier
(2)
,
Isabelle Touitou
(2, 10)
,
Guillaume Sarrabay
(1, 10, 2)
1
Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
2 CHU Montpellier
3 AP-HP Hôpital universitaire Robert-Debré [Paris]
4 Hôpital Necker - Enfants Malades [AP-HP]
5 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
6 Pathogénèse et contrôle des infections chroniques (PCCI)
7 Hôpital d'Instruction des Armées Legouest
8 CHU Trousseau [APHP]
9 Hôpital Gui de Chauliac [CHU Montpellier]
10 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
11 Oslo University Hospital [Oslo]
12 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
13 APHP, Groupe Hospitalier Cochin, Départementd’Hépatologie, Paris, France
14 UFR Sciences Fondamentales et Biomédicales [Sciences] - Université Paris Cité
15 Hôpital l'Archet
16 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
17 CHU Tenon [AP-HP]
18 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
19 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
20 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
21 CHV - Centre Hospitalier de Versailles André Mignot
2 CHU Montpellier
3 AP-HP Hôpital universitaire Robert-Debré [Paris]
4 Hôpital Necker - Enfants Malades [AP-HP]
5 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
6 Pathogénèse et contrôle des infections chroniques (PCCI)
7 Hôpital d'Instruction des Armées Legouest
8 CHU Trousseau [APHP]
9 Hôpital Gui de Chauliac [CHU Montpellier]
10 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
11 Oslo University Hospital [Oslo]
12 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
13 APHP, Groupe Hospitalier Cochin, Départementd’Hépatologie, Paris, France
14 UFR Sciences Fondamentales et Biomédicales [Sciences] - Université Paris Cité
15 Hôpital l'Archet
16 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
17 CHU Tenon [AP-HP]
18 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
19 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
20 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
21 CHV - Centre Hospitalier de Versailles André Mignot
Claire Duflos
- Fonction : Auteur
- PersonId : 18667
- IdHAL : claire-duflos
- ORCID : 0000-0002-7239-530X
Isabelle Melki
- Fonction : Auteur
- PersonId : 766552
- ORCID : 0000-0002-8057-333X
- IdRef : 158851897
Didier Bessis
- Fonction : Auteur
- PersonId : 907533
Hélène Martin
- Fonction : Auteur
- PersonId : 756024
- ORCID : 0000-0001-8318-3858
Sophie Georgin-Lavialle
- Fonction : Auteur
- PersonId : 764309
- IdHAL : sophie-georgin-lavialle
- ORCID : 0000-0001-6668-8854
- IdRef : 111766311
Alexandre Belot
- Fonction : Auteur
- PersonId : 949521
- ORCID : 0000-0003-4902-5332
- IdRef : 115823824
Guilaine Boursier
- Fonction : Auteur
- PersonId : 786342
- ORCID : 0000-0002-2903-3135
- IdRef : 165633123
Résumé
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