Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis

Abstract

Objective Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood‐onset polyarteritis nodosa (PAN), a primary “idiopathic” systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2. Methods The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting. Results Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody–associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely. Conclusion These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early‐onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.

Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach

“…in two patients carrying a homozygous deletion of the locus 22q11.1, harboring both copies of the il-17 receptor a (IL17RA) and the CECR1 gene, muco-cutaneous infections and dermatitis were observed (26). By contrast, Gibson et al (18) were not able to correlate genotype to phenotype in nine children diagnosed with dada2, thus assuming that apart from the ada2 mutations other factors such as modifying genes, epigenetic modifications and possibly environmental factors are also involved in the pathogenesis of dada2 and disease expressivity. Therefore, further studies are warranted in order to better understand the genotype-phenotype correlation in patients with dada2.…”

“…However, the disease severity was found to be highly varied from mild type of the disease limited to the skin, without any constitutional symptoms to severe, which was finally fatal in some cases (1). As regards the study conducted by Gibson et al (18), the authors suggested that arg8Trp may have benign consequences and both leu351Gln and ala357Thr probably damaging ones. It has been suggested that the clinical significance of novel variants cannot be assessed from their allele frequencies only (21).…”

“…in the present study, the authors sought to analyze the functional role of rare variants of either known (p.Gly47arg and p.Gly47ala) or novel (p.arg34Trp, p.leu351Gln and p.ala357Thr) of the ada2 protein, by using 3-d modeling and assessing the structural consequences of the respective amino acid substitutions. The identified variants showing a novel association with dada2 were initially predicted to be damaging (18). ada2 has been considered to be both the major extracellular adenosine deaminase and an adenosine deaminase-related growth factor (1).…”

“…recently, Gibson et al (18) performed the screening of an international registry of children with systemic primary vasculitis for variants in ada2 and the subsequent genotyping of 9 children identified with DADA2. By performing dna sequencing of the coding exons, they found rare variants of either known (p.Gly47arg and p.Gly47ala) or novel (p.arg8Trp, p.leu351Gln and p.ala357Thr) associations with dada2.…”

“…Moreover, they assessed the functional consequences of the identified variants by using specific ADA2 assays and immunoblotting. Prompted by these recent results, and considering the suggestion that screening ada2 among children with vasculitis rash, unclassifiable vasculitis (UCV), PAN, or unexplained early-onset CNS disease with systemic inflammation may enable an earlier diagnosis of dada2 (18), this study was performed in an attempt to further elucidate the functional significance of these mutations by using a structural biological approach.…”