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Phenotypic variability including Behçet's disease-like manifestations in DADA2 patients due to a homozygous c.973-2A>G splice site mutation
G.T. Van Well1, B. Kant2, A. Van Nistelrooij3, S. Sirma Ekmekci4, S.V. Henriet5, E. Hoppenreijs6, M. Van Deuren7, J. Van Montfrans8, S. Nierkens9, A. Gül10, M.E. Van Gijn11
- Department of Paediatrics and School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
- Department of Genetics, University Medical Centre Utrecht, The Netherlands.
- Department of Paediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands.
- Department of Genetics, Institute for Experimental Medicine, Istanbul University, Turkey.
- Department of Paediatric Infectious Diseases and Immunology, Amalia Children’s Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands.
- Department of Paediatric Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
- Department of Paediatric Immunology, University Medical Centre Utrecht, The Netherlands.
- Centre for Translational Immunology, University Medical Centre Utrecht, The Netherlands.
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Turkey. agul@istanbul.edu.tr
- Department of Genetics, University Medical Centre Groningen, The Netherlands. m.e.van.gijn@umcg.nl
CER12653
2019 Vol.37, N°6 ,Suppl.121
PI 0142, PF 0146
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PMID: 31856934 [PubMed]
Received: 04/08/2019
Accepted : 28/10/2019
In Press: 09/12/2019
Published: 09/12/2019
Abstract
OBJECTIVES:
To describe phenotypic and functional characteristics of patients with the homozygous c.973-2A>G splice site mutation in the adenosine deaminase 2 (ADA2) gene (rs139750129), resulting in deficiency of ADA2 (DADA2).
METHODS:
We present case synopses of six patients from three unrelated families. Clinical data were analysed and next-generation sequencing (NGS) was performed. We also tested for aberrant RNA splicing and measured ADA2 enzyme activity.
RESULTS:
One family had common DADA2 symptoms, whereas Behçet’s disease-like manifestations were observed in the other two families. We detected the homozygous c.973-2A>G splice site mutation in ADA2 in all patients tested. ADA2 enzyme activity was significantly lower in patients than in healthy controls, but no correlation between ADA2 activity levels and disease severity was observed. Aberrant splicing was detected in a minority of mRNA transcripts, but the formation of other, undetected, aberrant splicing products could not be excluded. Patients were treated with TNF-α inhibitors to prevent recurrence of inflammatory findings including cerebral vasculitis-associated stroke.
CONCLUSIONS:
We describe three families with the same homozygous splice site mutation in ADA2 and observed a novel combination of manifestations resembling Behçet’s disease. This further expands the range of phenotypes caused by ADA2 mutations, although no complete genotype-phenotype association could be determined. Even without active disease, the risk of stroke should be addressed in making decisions regarding treatment of DADA2 patients.
