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Genetic panel screening in patients with clinically unclassified systemic autoinflammatory diseases

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Abstract

Objective

Systemic autoinflammatory diseases (SAIDs) may not always present with typical clinical findings of a monogenic disease. We aimed to genetically screen and diagnose these clinically unclassified patients by next-generation sequencing (NGS) analysis.

Method

A total of 64 patients who had clinical findings of a periodic fever syndrome but did not meet the clinical diagnostic criteria for any SAID or had clinical findings for more than one monogenic SAID were identified as “clinically unclassified SAIDs.” NGS panel analysis, including 16 genes, was performed in these patients. Patients, who could not be classified as one of the defined SAID after the result of the NGS gene analysis, were identified as “undefined SAID.”

Results

The most common autoinflammatory symptoms in unclassified SAID patients were abdominal pain (60.9%), arthralgia (48.4%), urticarial rash (43.8%), myalgia (40.6%), oral aphthae (28.1%), and conjunctivitis (20.3%), respectively. In the result of the NGS gene panel screening, pathogenic, likely pathogenic variants, or VUS (variants of uncertain significance) were detected in 36 of 64 patients in at least one gene in the NGS panel. A total of 15 patients were diagnosed with a monogenic SAID according to both phenotypic and genotypic data; 12 patients as FMF, two patients as FCAS, and one patient as TRAPS, respectively. A total of 49 patients who did not meet the classification criteria including genetic results for a monogenic SAID were followed as undefined SAID.

Conclusions

The classification criteria described for SAIDs so far unfortunately do not cover all patients with signs of periodic fevers. The NGS gene panel appears to be a useful diagnostic tool for some of the patients with clinically unclassified SAID findings.

Key Points

• The classification criteria described for SAIDs do not cover all patients with signs of periodic fevers

• The use of the undefined SAID nomenclature will benefit clinicians for diagnosis and initiating early treatment

• The NGS panel appears to be a useful diagnostic tool in patients with clinically unclassified SAIDs

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Acknowledgments

We are grateful to all participating children and their families.

Author information

Authors and Affiliations

  1. Department of Pediatric Rheumatology, Umraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

    Ferhat Demir & Betül Sözeri

  2. Department of Pediatric Genetics, Umraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

    Özlem Akgün Doğan & Yasemin Kendir Demirkol

  3. Genomic Laboratory (GLAB), Umraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

    Kübra Ermiş Tekkuş, Sezin Canbek & Hamdi Levent Doğanay

  4. Department of Pediatric Rheumatology, Kanuni Sultan Süleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

    Şerife Gül Karadağ, Hafize Emine Sönmez & Nuray Aktay Ayaz

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  1. Ferhat Demir
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Contributions

B.S., F.D. and N.A.A. developed the concept and designed research; F.D., H.E.S., S.G.K., B.S., and N.A. performed research and acquired data; Ö.A.D., Y.K.D., K.E.T., S.C., and H.LD. analyzed data; F.D., B.S., N.A.A., Ö.A.D., Y.K.D., K.E.T., S.C., and H.L.D. interpreted data; F.D. and B.S. wrote and reviewed the manuscript.

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Correspondence to Ferhat Demir.

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Demir, F., Doğan, Ö.A., Demirkol, Y.K. et al. Genetic panel screening in patients with clinically unclassified systemic autoinflammatory diseases. Clin Rheumatol 39, 3733–3745 (2020). https://doi.org/10.1007/s10067-020-05108-1

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  • DOI: https://doi.org/10.1007/s10067-020-05108-1

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