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Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis
Author(s) -
Gibson Kristen M.,
Morishita Kimberly A.,
Dancey Paul,
Moorehead Paul,
Drögemöller Britt,
Han Xiaohua,
Graham Jinko,
Hancock Robert E. W.,
Foell Dirk,
Benseler Susanne,
Luqmani Rashid,
Yeung Rae S. M.,
Shenoi Susan,
Bohm Marek,
Rosenberg Alan M.,
Ross Colin J.,
Cabral David A.,
Brown Kelly L.
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40913
Subject(s) - vasculitis , medicine , systemic vasculitis , adenosine deaminase , polyarteritis nodosa , phenotype , allele , immunology , pathology , disease , gene , biology , genetics , adenosine
Objective Individuals with deficiency of adenosine deaminase 2 ( DADA 2), 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 DADA 2 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 ADA 2 . Methods The coding exons of ADA 2 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 ADA 2 enzyme assay and immunoblotting. Results Nine children with DADA 2 (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 ADA 2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA 2 (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 DADA 2 has extensive genotypic and phenotypic variability. Thus, screening ADA 2 among children with vasculitic rash, UCV , PAN , or unexplained, early‐onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA 2.