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

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.

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…Given the extremely variable phenotype of DADA2, the condition is probably underdiagnosed. Based on a cohort of 66 patients with suspected DADA2, of which 13 were confirmed to have DADA2, Rama et al proposed a decision tree for the diagnosis of ADA2 deficiency. The features best associated with a confirmatory DADA2 genotype included fever with neurologic or cutaneous manifestations (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 level with neurologic involvement (OR 6.63, P = 0.017) .…”

“…Given the extremely variable phenotype of DADA2, the condition is probably underdiagnosed. Based on a cohort of 66 patients with suspected DADA2, of which 13 were confirmed to have DADA2, Rama et al 92 proposed a decision tree for the diagnosis of ADA2 deficiency.…”

ADA2 deficiency in a patient with Noonan syndrome‐like disorder with loose anagen hair: The co‐occurrence of two rare syndromes

“…Anti‐TNF agents such as Etanercept, Adalimumab, and Infliximab have effects in reducing the frequency of stroke attacks and providing improvement in B cell number and functions (Moens et al, ; Schepp et al, ). However, these treatments may still remain insufficient in patients with severe cytopenia and immunodeficiency (Hashem et al, ; Rama et al, ) in whom stem cell transplantation may be an option in the presence of a suitable donor (Hashem, Kelly, Ganson, & Hershfield, ; Moens et al, ; Zhou et al, ).…”

ADA2 deficiency due to a novel structural variation in 22q11.1

“…ADA2 enzymatic activity was absent in the patient's circulating monocytes and plasma whereas parents showed a level lower than healthy donors (HD) (Figure A). The patient consistently responded to anti‐tumor necrosis factor treatment (etanercept) …”

“…Deficiency of the adenosine deaminase 2 ( ADA2 ) gene (OMIM#607575) (DADA2) (OMIM#615688) is a rare recessive autoinflammatory disease caused by bi‐allelic loss‐of‐function ADA2 mutations , showing a wide range of clinical manifestations, including cerebral stroke events and several kind of immune dysregulation . Interestingly, patients with typical DADA2 and complete enzymatic impairment, may present with only one or no ADA2 mutation, thus, suggesting involvement of null alleles …”