title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kazushi
authors.initials: K
authors.lastname: Izawa
authors.forename: Megumu K
authors.initials: MK
authors.lastname: Saito
authors.forename: Mio
authors.initials: M
authors.lastname: Sakuma
authors.forename: Koichi
authors.initials: K
authors.lastname: Oshima
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morimoto
authors.forename: Naotomo
authors.initials: N
authors.lastname: Kambe
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.forename: Mariëlle
authors.initials: M
authors.lastname: van Gijn
authors.forename: Joost
authors.initials: J
authors.lastname: Frenkel
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aróstegui
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
authors.forename: Rosa
authors.initials: R
authors.lastname: Merino
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ibañez
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pontillo
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Imagawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kawai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasumi
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D009030:Mosaicism / Q000706:statistics & numerical data*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human