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Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study

  • Genes and Disease
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A Correction to this article was published on 18 March 2019

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Abstract

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle–Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.

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Change history

  • 18 March 2019

    The second affiliation of the corresponding author Eda Tahir Turanlı was incorrectly published as İstanbul Medeniyet University instead of Istanbul Technical University.

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Funding

This study was funded by Istanbul University Scientific Research Fund (Grants: 49820 and BYP-2017-22876).

Author information

Authors and Affiliations

  1. Department of Molecular Biology-Genetics and Biotechnology, Dr. Orhan Öcalgiray Molecular Biology-Biotechnology and Genetics Research Centre, Graduate School of Science, Engineering and Technology, İstanbul Technical University, Ayazağa Campus, Maslak, 34469, Istanbul, Turkey

    İlker Karacan, Ayşe Balamir, Aslı Kireçtepe Aydın, Elif Everest, Seyit Zor, Merve Özkılınç Önen & Eda Tahir Turanlı

  2. Department of Molecular Biology and Genetics, İstanbul Medeniyet University, Istanbul, Turkey

    İlker Karacan & Eda Tahir Turanlı

  3. Division of Rheumatology, Department of Internal Medicine, Cerrahpaşa Medical Faculty, İstanbul University-Cerrahpaşa, Istanbul, Turkey

    Serdal Uğurlu, Emire Seyahi & Huri Özdoğan

  4. Department of Medical Biology, Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Selçuk Daşdemir

  5. Department of Pediatric Nephrology, Faculty of Medicine, Istinye University, Istanbul, Turkey

    Ozan Özkaya

  6. Department of Pediatric Rheumatology, Ümraniye Training and Research Hospital, Istanbul, Turkey

    Betül Sözeri

  7. Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Gazi University, Ankara, Turkey

    Abdurrahman Tufan

  8. Department of Pediatric Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey

    Deniz Gezgin Yıldırım

  9. Department of Pediatric Rheumatology, Faculty of Medicine, Pamukkale University, Denizli, Turkey

    Selçuk Yüksel

  10. Department of Pediatric Rheumatology, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey

    Nuray Aktay Ayaz & Mustafa Çakan

  11. Department of Pediatric Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Rukiye Eker Ömeroğlu

  12. Department of Pediatric Rheumatology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey

    Kübra Öztürk

  13. Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey

    Oğuz Söylemezoğlu

  14. Department of Pediatric Rheumatology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    Sezgin Şahin, Kenan Barut, Amra Adroviç & Özgür Kasapçopur

Authors
  1. İlker Karacan
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  2. Ayşe Balamir
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  3. Serdal Uğurlu
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  4. Aslı Kireçtepe Aydın
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  5. Elif Everest
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  6. Seyit Zor
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  7. Merve Özkılınç Önen
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  8. Selçuk Daşdemir
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  10. Betül Sözeri
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  11. Abdurrahman Tufan
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  12. Deniz Gezgin Yıldırım
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  13. Selçuk Yüksel
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  14. Nuray Aktay Ayaz
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  15. Rukiye Eker Ömeroğlu
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  16. Kübra Öztürk
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  17. Mustafa Çakan
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  18. Oğuz Söylemezoğlu
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  19. Sezgin Şahin
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  20. Kenan Barut
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  25. Eda Tahir Turanlı
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Contributions

İK: analysis and interpretation of the genomic data, drafting the work and critically revising the final version of the study. AB: laboratory genome analysis of the sample, drafting the work, checked the accuracy of the genotyping in line with phenotypic data. SU: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. AKA: laboratory genome analysis of the sample, drafting the work, checked the accuracy of the genotyping in line with phenotypic data. EE: analysis and interpretation of the genomic data, drafting the work. SZ: analysis and interpretation of the genomic data, drafting the work. MÖÖ: laboratory genome analysis of the sample, drafting the work, checked the accuracy of the genotyping in line with phenotypic data. SD: contributed genome analysis and drafting the work. OÖ: contributed samples to the study, analysed the genotype–phenotype correlations and revise the study. BS: contribute samples to the study, analysed the genotype–phenotype correlations and revised the study. AT: contributed samples to the study, analysed the genotype–phenotype correlations and critically revised the study. DGY: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. SY: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. NAA: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. RE: contributes samples to the study, analysed the genotype–phenotype correlations and revised the study. KÖ: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. MÇ: contribute samples to the study, analysed the genotype–phenotype correlations and revised the study. OS: contribute samples to the study, analysed the genotype–phenotype correlations and revised the study. SŞ: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. KB: contribute samples to the study, analysed the genotype–phenotype correlations and revised the study. AA: contributed samples to the study, analysed the genotype–phenotype correlations and revise the study. ES: contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. HÖ contributed and initiated the study and its design, contributed samples to the study, analysed the genotype–phenotype correlations and revised the study. ÖK: contributed and initiated the study and its design, contributed samples to the study, analysed the genotype–phenotype correlations and critically revised the study, aided in finding funds of the study. ETT: contributed and initiated the study and its design, analysed the genotype–phenotype correlations, did bioinformatic and statistical analysis and critically revised the study, aided in finding funds of the study.

Corresponding author

Correspondence to Eda Tahir Turanlı.

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All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Ethics Review Committee of XXXXXXX (approval number and dates: B.30.2.İST.0.30.90.00/19756, 3 July 2012 and 83045809-604.01.02, 6 December 2016). This article does not contain any studies with animals performed by any of the authors.

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Karacan, İ., Balamir, A., Uğurlu, S. et al. Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study. Rheumatol Int 39, 911–919 (2019). https://doi.org/10.1007/s00296-019-04252-5

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