Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France.
BACKGROUND
Cryopyrin-associated periodic syndromes (CAPS) consist of a continuum of autoinflammatory diseases caused by a defect in interleukin 1β regulation. Although symptoms may vary widely, the discovery, in 2001, of the gene involved (NLRP3) has dramatically helped diagnosis.


OBJECTIVE
To define the spectrum and prevalence of NLRP3 mutations in France and to delineate initial criteria before molecular analysis.


METHODS
Retrospective review (2001-9) of genetic analysis data and request forms of patients living in France with an NLRP3 mutation since the set up of CAPS molecular diagnosis by the three French laboratories providing this test (GenMAI network).


RESULTS
Over 800 analyses of this gene have been conducted, identifying 135 cases with an NLRP3 mutation (55 probands; 33 multiplex families); the estimated prevalence in France was equal to 1/360 000. A total of 21 different sequence variants were detected, among which four are common and nine are new mutations.


CONCLUSIONS
Although the number of NLRP3 test requests has doubled over the past 5 years, genetic screening has not contributed to enhanced detection of new index cases each year. There are two possible reasons for this: (i) no clinical prerequisite for genetic diagnosis and (ii) few new large families are now identified (unlike the initial study based on a selection by linkage). A set of initial clinical criteria have been drawn up which it is recommended should be fulfilled before a patient is tested: at least three recurrent bouts, age at disease onset < 20 years and elevated levels of C-reactive protein, especially in individuals with urticaria and moderate fever.
Correspondence to Isabelle Touitou, Unité Médicale des Maladies Auto-Inflammatoires, CHRU Montpellier and Université Montpellier 1, Montpellier, France.
L
L
Cuisset
I
I
Jeru
B
B
Dumont
A
A
Fabre
E
E
Cochet
J
J
Le Bozec
M
M
Delpech
S
S
Amselem
I
I
Touitou
D000293:Adolescent; D017668:Age of Onset; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D056587:Cryopyrin-Associated Periodic Syndromes / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010641:Phenotype; D012008:Recurrence; D012189:Retrospective Studies; D055815:Young Adult
D015415:Biomarkers; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D002097:C-Reactive Protein