BRIEF RESEARCH REPORT article
Front. Pediatr.
Sec. Pediatric Rheumatology
Volume 13 - 2025 | doi: 10.3389/fped.2025.1598748
Somatic NLRP3 mosaicism in patients with "mutation-negative" CAPS: insights from a single centre UK cohort
Provisionally accepted
Sonia Melo Gomes1*
Juan Ignacio Arostegui2
Anna Mensa Vilaro2Ebun Omoyinmi3
Ying Hong3Dara McCreary3
Dorota Monika Rowczenio3Philip Hawkins3
Paul Anthony Brogan1,3*- 1Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
- 2Hospital Clinic of Barcelona, Barcelona, Catalonia, Spain
- 3University College London, London, England, United Kingdom
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Knowledge about mosaicism in cryopyrin-associated periodic syndromes (CAPS) has expanded significantly with the use of next generation sequencing technologies.The aim of this study was to assess the contribution of mosaicism in a paediatric cohort of patients with a clinical diagnosis of CAPS and no NLRP3 mutations identified through conventional DNA sequencing.Mosaicism was assessed by amplicon-based deep sequencing (ADS) on DNA extracted from different tissues overtime. Targeted gene panels (TGPs) and whole-exome sequencing (WES) were used for comparison of detection methods.In 40% (4/10) of the cohort a post-zygotic NLRP3 mutation leading to somatic mosaicism was found by ADS. Three of the detected NLRP3 mutations had been previously described only in somatic form and one both as germline and somatic. Mean mutant allelic frequencies (MAF) at diagnosis varied between 3.1-14.5% in whole blood, with all mutations being present in other tissues tested. In 3 patients, mosaicism was evaluated over time in whole blood, with results confirming mosaicism stability in 2 patients, and a MAF increase in 1 patient (from 1.9% to 5%). TGPs identified 4/4 cases of mosaicism whilst WES detected only 1/3.Somatic NLRP3 mosaicism was present in 40% of this paediatric cohort, confirming the key role of this phenomenon in disease pathogenesis and in genetic confirmation of CAPS diagnosis. MAFs can be extremely low, which warrants caution regarding lower detection limits of the sequencing techniques utilized. Mosaicism level may vary over time in some patients, with diagnostic and potential therapeutic implications.
Keywords: Mosaicism, CAPS, NLRP3, NGS - next generation sequencing, Mosaicism distribution, Mosaicism stability
Received: 23 Mar 2025; Accepted: 20 May 2025.
Copyright: © 2025 Melo Gomes, Arostegui, Mensa Vilaro, Omoyinmi, Hong, McCreary, Rowczenio, Hawkins and Brogan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Sonia Melo Gomes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, United Kingdom
Paul Anthony Brogan, University College London, London, WC1E 6BT, England, United Kingdom
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