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.
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 approximately 55-60% 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 approximately 30-38% 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.


CONCLUSIONS
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.
Aróstegui
Juan I
JI
Hospital Clínic, 08036 Barcelona, Spain. jiaroste@clinic.ub.es
Lopez Saldaña
Ma Dolores
MD
Pascal
Mariona
M
Clemente
Daniel
D
Aymerich
Marta
M
Balaguer
Francesc
F
Goel
Ajay
A
Fournier del Castillo
Concepción
C
Rius
Josefa
J
Plaza
Susana
S
López Robledillo
Juan Carlos
JC
Juan
Manel
M
Ibañez
Mercedes
M
Yagüe
Jordi
J
D002352:Carrier Proteins / Q000235:genetics*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D017931:DNA Primers; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D009030:Mosaicism; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D015183:Restriction Mapping; D014581:Urticaria / Q000235:genetics
D002352:Carrier Proteins; D017931:DNA Primers; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D004247:DNA