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

Anemia is characterized by a reduction in red blood cells, and hereditary forms are associated with underlying genetic factors. We investigated a Chinese family in which the proband and his daughter had anemia, using next-generation sequencing (NGS) and whole-exome sequencing (WES) to characterize germline and somatic variants. A heterozygous germline STAT5B c.1591G > A (p.Val531Met) variant of uncertain significance (VUS) was identified across three generations; anemia occurred only in the proband and his daughter, who also had distinct low clonal burden somatic STAT3 variants. The proband was diagnosed with T-cell large granular lymphocytic leukemia (T-LGLL) with erythroid hypoplasia, whereas his daughter had progressive erythroid hypoplasia but did not meet diagnostic criteria for T-LGLL. Both patients were administered sirolimus for suspected immune-mediated erythroid suppression and achieved hematologic improvement. These findings highlight how advances in NGS and WES can improve the detection of clinically relevant variants in families with anemia, supporting earlier risk-reducing interventions and more personalized therapeutic strategies for affected individuals and at-risk relatives.