High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: Results of an international multicenter collaborative study

Abstract

Objective Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal‐onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain‐of‐function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease‐causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation‐negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. Methods An international case–control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation‐negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype–phenotype associations. Results Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease‐causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype‐matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. Conclusion Somatic NLRP3 mutations were identified in 69.2% of patients with mutation‐negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.