Journal of clinical laboratory analysis · 2026
Calreticulin Type 26 Mutation in Myelofibrosis: A Rare Variant With Diagnostic Challenges.
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Maltese Teresa, Raffa Giuseppina, Stagno Fabio, Leanza Rossana, Barone Paola, Allegra Alessandro, Pollicino Teresa
Аннотация
BACKGROUND: Myeloproliferative neoplasms (MPNs) are clonal hematologic disorders commonly driven by mutations in JAK2, MPL, or CALR. Because routine CALR assays are largely optimized for the canonical Type 1 and Type 2 exon 9 variants, rare noncanonical mutations may be missed, creating diagnostic challenges.
METHODS: We report the case of a 78-year-old woman diagnosed with an MPN in 2016 and treated with hydroxyurea. Initial molecular testing included JAK2 V617F screening and PCR-based fragment-length analysis by capillary electrophoresis for CALR exon 9 indels, both of which yielded negative results. After clinical progression, in 2024, repeat hematologic evaluation, bone marrow biopsy, Sanger sequencing, cloning, and next-generation sequencing (NGS) were performed.
RESULTS: Disease progression was associated with marked thrombocytosis, leukocytosis, microcytic anemia, and bone marrow findings consistent with primary myelofibrosis. Advanced molecular testing identified a heterozygous CALR c.1122delG frameshift mutation (Type 26), a rare exon 9 variant not detected by the initial assay. Cloning confirmed heterozygosity, and NGS demonstrated a variant allele frequency of 43%. An additional CBL splice-site mutation (VAF 17%) was also detected.
CONCLUSION: This case highlights the limitations of routine assays focused on common CALR mutations and supports comprehensive sequencing-based approaches for detecting rare CALR variants. Expanded molecular testing may improve diagnostic accuracy and clinical classification in MPNs.
METHODS: We report the case of a 78-year-old woman diagnosed with an MPN in 2016 and treated with hydroxyurea. Initial molecular testing included JAK2 V617F screening and PCR-based fragment-length analysis by capillary electrophoresis for CALR exon 9 indels, both of which yielded negative results. After clinical progression, in 2024, repeat hematologic evaluation, bone marrow biopsy, Sanger sequencing, cloning, and next-generation sequencing (NGS) were performed.
RESULTS: Disease progression was associated with marked thrombocytosis, leukocytosis, microcytic anemia, and bone marrow findings consistent with primary myelofibrosis. Advanced molecular testing identified a heterozygous CALR c.1122delG frameshift mutation (Type 26), a rare exon 9 variant not detected by the initial assay. Cloning confirmed heterozygosity, and NGS demonstrated a variant allele frequency of 43%. An additional CBL splice-site mutation (VAF 17%) was also detected.
CONCLUSION: This case highlights the limitations of routine assays focused on common CALR mutations and supports comprehensive sequencing-based approaches for detecting rare CALR variants. Expanded molecular testing may improve diagnostic accuracy and clinical classification in MPNs.