From bedside to bench and back: discovery of a novel missense variant in NLRP3 causing atypical CAPS with hearing loss as the primary presentation, responsive to anti-IL-1 therapy

Cryopyrin-associated periodic syndromes (CAPS) also known as NLRP3-associated auto-inflammatory diseases, are a spectrum of rare auto-inflammatory diseases caused by gain-of-function mutations in the NLRP3 gene, resulting in inflammasome hyper-activation and dysregulated release of Interleukin-1β (IL-1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) due to cochlear auto-inflammation which, in rare cases, may be the sole manifestation. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting autosomal dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821:c.1790G>A, p.Ser597Asn). To do so, we conducted an ex vivo functional assessment of the NLRP3 inflammasome in carries (n=10) and healthy family members (n=5). The assay revealed hyper-activation of the inflammasome among carriers, supporting the hypothesis that this missense variant is a pathogenic gain-of-function mutation. Administration of anti-IL-1 therapy resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1-3 months of treatment. Our findings highlight the crucial role of early diagnosis and treatment of hearing loss due to hyperactivation of the inflammasome with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high and ultrahigh frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement GM acknowledges funding from US-BSF grant #2017176, ISF grant #2174/22. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics committee of the Rabin medical center (Schneider Children's medical center of Israel), Petach-Tikva, Israel gave ethical approval for this work (IRB#0941-20-RMC). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors