@article {1824, title = {High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.}, journal = {Arthritis Rheum}, volume = {63}, year = {2011}, month = {2011 Nov}, pages = {3625-32}, 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 {\textpm} SD 12.1 {\textpm} 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.

}, keywords = {Adolescent, Adult, Carrier Proteins, Case-Control Studies, Child, Child, Preschool, Cryopyrin-Associated Periodic Syndromes, Female, Genetic Association Studies, Humans, Infant, Male, Mosaicism}, issn = {1529-0131}, doi = {10.1002/art.30512}, author = {Tanaka, Naoko and Izawa, Kazushi and Saito, Megumu K and Sakuma, Mio and Oshima, Koichi and Ohara, Osamu and Nishikomori, Ryuta and Morimoto, Takeshi and Kambe, Naotomo and Goldbach-Mansky, Raphaela and Aksentijevich, Ivona and de Saint Basile, Genevi{\`e}ve and Neven, B{\'e}n{\'e}dicte and van Gijn, Mari{\"e}lle and Frenkel, Joost and Ar{\'o}stegui, Juan I and Yag{\"u}e, Jordi and Merino, Rosa and Iba{\~n}ez, Mercedes and Pontillo, Alessandra and Takada, Hidetoshi and Imagawa, Tomoyuki and Kawai, Tomoki and Yasumi, Takahiro and Nakahata, Tatsutoshi and Heike, Toshio} }