Addressing Diagnostic Gaps in Autoinflammatory Diseases

Clinicians often face diagnostic dilemmas when patients present with classic symptoms of Familial Mediterranean Fever (FMF). Traditional genetic tests often yield negative results in these cases. This gap occurs because standard fragment analysis screens only a limited set of common mutations. Consequently, using NGS for FMF diagnosis has emerged as a transformative approach to uncover hidden genetic variants. A recent retrospective study demonstrates that comprehensive sequencing significantly improves diagnostic accuracy. It sequences the entire MEFV gene and additional autoinflammatory genes to provide a complete picture.

The study evaluated 320 patients meeting FMF clinical criteria. These individuals lacked a confirmatory genotype through traditional 16-variant screening. By employing a broader panel, researchers identified pathogenic variants in 34% of these cases. Specifically, the NGS technology detected rare MEFV variants like c.380A C and c.428 G T. Routine assays frequently miss these specific mutations. Furthermore, the analysis revealed compound heterozygosity in several patients. This provides a clearer molecular explanation for their inflammatory symptoms and periodic fever episodes.

Enhancing Clinical Accuracy with NGS for FMF diagnosis

Beyond the primary MEFV gene, researchers identified variants in other related genes. These included TNFRSF1A, NOD2, and PSTPIP1 in 45 patients. These findings suggest that modifier effects or oligogenic inheritance may drive FMF-like presentations. Moreover, clinical reevaluation showed that these patients exhibited diverse symptoms. They also showed varying responses to colchicine treatment. Therefore, a comprehensive genetic profile allows physicians to tailor therapeutic strategies. It also helps predict long-term complications like systemic amyloidosis. In contrast to narrow screening, this method offers a deeper understanding of genetic heterogeneity in autoinflammatory phenotypes.

How does NGS improve FMF diagnosis?

NGS for FMF diagnosis allows for the sequencing of the entire MEFV gene and other related autoinflammatory genes. This comprehensive approach detects rare variants and compound mutations that traditional screening panels often overlook.

Can mutations in genes other than MEFV cause FMF-like symptoms?

Yes, variants in genes such as TNFRSF1A, NOD2, and PSTPIP1 can result in clinical presentations that mimic FMF. Identifying these variants helps clinicians understand the broader genetic heterogeneity and adjust treatment plans accordingly.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or a professional relationship. Always seek the advice of a qualified healthcare provider for any questions regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Karaer D et al. Next-generation sequencing reveals genetic heterogeneity in MEFV-Negative or heterozygous Familial Mediterranean fever: a retrospective study. Expert Rev Clin Immunol. 2026 Apr 19. doi: 10.1080/1744666X.2026.2660767. PMID: 42001281.

Richard J, et al. NextGen sequencing (NGS) panel for hereditary recurrent fevers: mutation spectrum, novel mutations, and evidence for re-classification of common variants. Annals of the Rheumatic Diseases. 2015.

Bozgeyik E, et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020.