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Brief Report: Whole‐Exome Sequencing Revealing Somatic NLRP3 Mosaicism in a Patient With Chronic Infantile Neurologic, Cutaneous, Articular Syndrome
Author(s) -
Omoyinmi Ebun,
Melo Gomes Sónia,
Standing Ariane,
Rowczenio Dorota M.,
Eleftheriou Despina,
Klein Nigel,
Aróstegui Juan I.,
Lachmann Helen J.,
Hawkins Philip N.,
Brogan Paul A.
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38217
Subject(s) - sanger sequencing , exome sequencing , massive parallel sequencing , exome , genetics , dna sequencing , germline mutation , mutation , missense mutation , biology , medicine , gene
Objective To identify the genetic cause of chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) using whole‐exome sequencing in a child who had typical clinical features but who was NLRP3 mutation negative based on conventional Sanger sequencing. Methods We performed whole‐exome sequencing on DNA from peripheral blood, using Illumina TruSeq Exome capture and the HiSeq sequencing platform. Exome data were analyzed in the Galaxy Web‐based suite. Whole‐exome sequencing findings were confirmed by massively parallel sequencing. Results Analysis of variants in known autoinflammatory genes led to the identification of the pathogenic p.F556L NLRP3 missense mutation in 17.7% of Illumina reads (25 of 141). No new candidate genes were identified. Massively parallel sequencing of DNA from peripheral blood (performed in duplicate) unequivocally confirmed the presence of this mutation in 14.5% of alleles. Reexamination of the original Sanger chromatograms revealed a small peak at nucleotide position c.1698 corresponding to the mutated allele. This had initially been regarded as background noise, but in retrospect is completely consistent with somatic mosaicism for the p.F556L NLRP3 mutation in this child with CINCA syndrome. Conclusion This is the first description of somatic NLRP3 mosaicism detected using whole‐exome sequencing in a “mutation‐negative” patient with CINCA syndrome. Our findings suggest that whole‐exome sequencing could be an important diagnostic tool for detecting somatic mosaicism, as well as for the discovery of novel causative gene mutations, in patients with clinical features of cryopyrin‐associated periodic syndromes who are NLRP3 mutation negative by conventional sequencing. This approach could also be applicable to patients with other autosomal‐dominant autoinflammatory diseases characterized by gain‐of‐function mutations who are mutation negative by conventional Sanger sequencing.