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.
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 syndromepatients, 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 syndromepatients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndromepatients 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.
Authors: Ivona Aksentijevich; Christopher D Putnam; Hal M Hoffman; Daniel L Kastner; Elaine F Remmers; James L Mueller; Julie Le; Richard D Kolodner; Zachary Moak; Michael Chuang; Frances Austin; Raphaela Goldbach-Mansky Journal: Arthritis Rheum Date: 2007-04
Authors: Raphaela Goldbach-Mansky; Natalie J Dailey; Scott W Canna; Ana Gelabert; Janet Jones; Benjamin I Rubin; H Jeffrey Kim; Carmen Brewer; Christopher Zalewski; Edythe Wiggs; Suvimol Hill; Maria L Turner; Barbara I Karp; Ivona Aksentijevich; Frank Pucino; Scott R Penzak; Margje H Haverkamp; Leonard Stein; Barbara S Adams; Terry L Moore; Robert C Fuhlbrigge; Bracha Shaham; James N Jarvis; Kathleen O'Neil; Richard K Vehe; Laurie O Beitz; Gregory Gardner; William P Hannan; Robert W Warren; William Horn; Joe L Cole; Scott M Paul; Philip N Hawkins; Tuyet Hang Pham; Christopher Snyder; Robert A Wesley; Steven C Hoffmann; Steven M Holland; John A Butman; Daniel L Kastner Journal: N Engl J Med Date: 2006-08-10 Impact factor: 91.245
Authors: Cailin H Sibley; Nikki Plass; Joseph Snow; Edythe A Wiggs; Carmen C Brewer; Kelly A King; Christopher Zalewski; H Jeffrey Kim; Rachel Bishop; Suvimol Hill; Scott M Paul; Patrick Kicker; Zachary Phillips; Joseph G Dolan; Brigitte Widemann; Nalini Jayaprakash; Frank Pucino; Deborah L Stone; Dawn Chapelle; Christopher Snyder; John A Butman; Robert Wesley; Raphaela Goldbach-Mansky Journal: Arthritis Rheum Date: 2012-07
Authors: S Tsuji; H Matsuzaki; M Iseki; A Nagasu; H Hirano; K Ishihara; N Ueda; Y Honda; T Horiuchi; R Nishikomori; Y Morita; T Mukai Journal: Clin Exp Immunol Date: 2019-09-04 Impact factor: 4.330