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Background: Autoinflammatory and immuno-hematological diseases have experienced significant expansion due to advances in genetics and next-generation sequencing (NGS) technologies. Currently, nearly 100 autoinflammatory diseases have been described thanks to novel sequencing approaches. In hematology, NGS panels targeting myeloid and lymphoid genes allow precise identification of somatic mutations, which are critical for prognosis. The current strategy in immunoinflammatory diseases increasingly relies on precision diagnostics using whole exome sequencing (WES) and, more recently, whole genome sequencing (WGS). Unfortunately, these techniques are often unavailable in emerging countries such as Tunisia, where consanguinity is highly prevalent. Collaborations enabling shipment of patient samples for targeted gene panels or WES have partially addressed this gap.
Objectives: To evaluate the diagnostic yield of NGS, either targeted panels or WES, in North African patients with suspected autoinflammatory diseases.
Methods: We performed targeted NGS panels or WES in patients with suspected autoinflammatory diseases after excluding infectious and autoimmune etiologies
Results: Eleven North African patients were included (sex ratio 1.16), with consanguinity reported in 4/11 patients. The median age at symptom onset was 20 years (range 1–76), and the median age at diagnosis was 39 years (range 29–82). Recurrent fever was observed in 10/11 patients, inflammatory arthralgias in 9/11, interstitial lung disease in 3/11, mediastinal or abdominal lymphadenopathy in 4/11, hepatomegaly in 7/11, recurrent abdominal pain in 3/11, and peripheral neuropathy in 1 patient. Laboratory findings included a median white blood cell count of 7,410/mm 3 (3,770–12,546), mean hemoglobin 11 g/dL, median MCV 80 fL (67–110), and median lymphocytes 975/mm 3 (280–1,646). All patients had elevated CRP (median 55 mg/L, range 23–123). ANA positivity was observed in 3 patients. Prior to genetic diagnosis, 7 patients received corticosteroids, 3 colchicine, and 1 an anti-IL1 therapy. Genetic analyses included WES (n=6), myeloid NGS panel (n=2), autoinflammatory disease panel (n=2), and UBA1 gene sequencing with NGS (n=1).
Genetic diagnoses included:
CANDLE syndrome due to a homozygous PSMB8 mutation (c.-30_16del) in a patient initially diagnosed with systemic lupus erythematosus.
Homozygous COL7A mutation (p.Gly1483Asp) in a patient with bullous skin lesions and chronic inflammation.
Homozygous SDR9C7 mutation in a patient with ichthyosis initially diagnosed with dermatomyositis.
Interstitial deletion on chromosome 17q affecting 18 OMIM genes in a patient with primary immunodeficiency.
Heterozygous RTEL1 mutation (Arg986Ter) in a patient with PID and myelodysplastic syndrome.
Homozygous pathogenic CECR1 mutation in a patient with extracapillary glomerulonephritis, renal failure, paresthesia, and livedo, consistent with DADA2.
Macrocytic anemia in 2 patients: one with UBA1 M41T mutation, and another with additional mutations in JAK2, SRSF2, RUNX1, and ZRSR2 .
Two patients with recurrent fever and abdominal pain resembling familial Mediterranean fever showed partial response to colchicine; targeted NGS panels for autoinflammatory disease were negative.
One patient with anemia and chronic inflammation, myloid panel did not reveal any mutation.
Conclusions: NGS, including targeted panels and WES, demonstrates significant diagnostic utility in patients from emerging countries with suspected autoinflammatory diseases, particularly in contexts of high consanguinity and atypical clinical presentations. Early genetic diagnosis enables personalized treatment strategies, avoids misdiagnosis, and may guide therapy in otherwise challenging cases. Collaborative access to advanced sequencing technologies is essential to improve outcomes in resource-limited settings.
REFERENCES: NIL.
Acknowledgments: NIL.
Disclosure of Interests: None declared.