A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal‐onset multisystem inflammatory disease: Novel evidence of the role of low‐level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases

Abstract

Objective. Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a severe, early-onset autoinflammatory disease characterized by an urticaria-like rash, arthritis/ arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin-1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease-causing mutations in only ϳ55-60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID.Methods. Clinical data, laboratory results, and information on treatment outcomes were gathered through direct interviews. Exhaustive genetic studies, including Sanger method sequencing, subcloning, restriction fragment length polymorphism assay, and pyrosequencing, were performed.Results. The patient's CINCA/NOMID was diagnosed based on clinical features (early onset of the disease, urticaria-like rash, knee arthropathy, and dysmorphic features). The patient has exhibited a successful response to anakinra within the last 28 months. Analysis of NLRP3 identified a novel heterozygous variant (p.D303H) that was detected in ϳ30-38% of circulating leukocytes. The absence of this variant in healthy controls and in the patient's parents suggested a de novo true disease-causing mutation. Additional analyses showed that this novel mutation was present in both leukocyte subpopulations and epithelial cells.Conclusion. Our findings identify the novel p.D303H NLRP3 variant in a Spanish patient with CINCA/NOMID as a new disease-causing mutation, which was detected as a somatic, nongermline mutation in hematopoietic and nonhematopoietic cell lineages. Our data provide new insight into the role of low-level mosaicism in NLRP3 as the pathophysiologic mechanism underlying cryopyrin-associated periodic syndrome.

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

“…Low-level mosaicism causing disease was also reported in a patient with clinical NOMID who had a de novo somatic genetic mutation (D303H) in CIAS1 in 30% to 38% of circulating leukocytes and epithelial cells [21]. The extent to which somatic mosaicism in NOMID/CINCA can account for mutation-negative cases and the cell types carrying the mutations are areas of active investigation.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…This implies that some missense mutations in the NLRP3 gene can exert a dominant phenotype leading to CAPS even when NLRP3 is expressed by less than 25% of the cells in mosaic patients. 81,84 This could be due to the positive feedback loop sustained by the IL-1/IL-1R axis.…”

Clinical and Molecular Genetic Features of Autoinflammatory Syndromes in Children

“…Кроме того, следует подчеркнуть, что наиболее важным этапом при анализе функциональной значимости не описанных ранее мутаций являются эксперименты на клеточных моделях [21]. Вместе с тем данные ряда исследова-ний показывают, что генетический анализ подтверждает лишь 30-40% клинически установленных диагнозов [22].…”