Diagnosis of NLRP3 somatic mosaicism in CINCA/NOMID patients using next-generation sequencing

Abstract

Background Chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID) is characterized by urticarial rash, neurological manifestations and arthropathy. This dominantly-inherited systemic autoinflammatory disease is provoked by heterozygous germline gain-of-function NLRP3 mutations, although conventional genetic analyses failed to detect diseasecausing mutations in approximately 40% of patients. In these patients, NLRP3 somatic mosaicism was reported to be disease-causing and recently, high incidence of NLRP3 somatic mosaicism was reported in the international study. In the study, subcloning and Sanger sequencing were used to detect NLRP3 somatic mosaicism. However, the method requires time-consuming sample preparation and enormous cost to run enough sequencing per sample to detect low-level somatic mosaicism.