Germline STAT5B and somatic STAT3 variants converge in a family’s inherited anemia

A single case report published in Annals of Hematology describes a Chinese family in which two generations carried the same inherited STAT5B variant, yet only the two members who additionally acquired somatic STAT3 variants developed anemia. The finding, based on next-generation sequencing and whole-exome sequencing of the proband and his relatives, raises the question of whether the combination of these two genetic events, rather than either alone, drove the blood disorder observed in the father and daughter.

The inherited change was a heterozygous germline STAT5B c.1591G>A variant, resulting in a p.Val531Met amino acid substitution, and it was classified as a variant of uncertain significance. This variant was detected across three generations of the family, but anemia appeared only in the proband and his daughter. Both of these affected individuals also carried distinct somatic STAT3 variants with a low clonal burden, a pattern the authors suggest may explain why the disease manifested in them and not in relatives who carried only the germline variant.

The clinical pictures differed between the two patients. The proband was diagnosed with T-cell large granular lymphocytic leukemia with erythroid hypoplasia, a condition in which malignant T-cell expansions are associated with suppressed red blood cell production. His daughter showed progressive erythroid hypoplasia but did not meet the diagnostic criteria for T-LGLL. Despite this difference, both patients received sirolimus on the suspicion that immune-mediated suppression of erythropoiesis was contributing to their anemia, and both achieved hematologic improvement with the treatment.

The authors present these observations as an illustration of how advances in next-generation sequencing and whole-exome sequencing can uncover clinically relevant variant combinations in families with anemia. In their view, characterizing both inherited and acquired variants in affected relatives may support earlier risk-reducing interventions and more personalized therapeutic strategies for patients and at-risk family members. As a single-family case report, the findings document an association in one kindred and do not establish how frequently this combination occurs or whether it is causally responsible for the anemia, but they underline the value of paired germline and somatic sequencing in hereditary blood disorders.

Subject of Research: Co-occurrence of a germline STAT5B variant and somatic STAT3 variants in a family with hereditary anemia

Article Title: Coexistence of STAT5B germline variant and STAT3 somatic variant in familial anemia: coincidence or clinically relevant?

Article References: Zheng, R., Zhang, M., Yang, X., Hong, Y., Li, H., Shen, Y., Zhou, Y., Wu, D., & Shen, Y. (2026). Coexistence of STAT5B germline variant and STAT3 somatic variant in familial anemia: coincidence or clinically relevant?. Annals of Hematology. https://doi.org/10.1007/s00277-026-07331-3

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07331-3

Keywords: STAT5B, STAT3, anemia, T-cell large granular lymphocytic leukemia, erythroid hypoplasia, whole-exome sequencing, next-generation sequencing, variant of uncertain significance, sirolimus, familial anemia, case report, hematology