Inherited Anemia: A Contemporary Clinical and Lab Review

Abstract

Inherited anemias represent a diverse group of genetic disorders characterized by impaired red blood cell production, increased destruction, or abnormal hemoglobin synthesis. This review provides a comprehensive overview of the contemporary clinical landscape, diagnostic workflows, and therapeutic advancements for both major and rare inherited anemias. Major hemoglobinopathies, including thalassemia and sickle cell disease (SCD), continue to impose a significant global health burden, while rare conditions such as hereditary hemolytic anemias (HHAs), congenital dyserythropoietic anemias (CDAs), and Diamond–Blackfan anemia (DBA) present unique diagnostic challenges. Recent years have seen a paradigm shift in laboratory investigations, primarily driven by the integration of next-generation sequencing (NGS) and third-generation sequencing (TGS) into clinical practice. These technologies have revolutionized the identification of causative variants, particularly in complex or multiallelic cases that elude traditional biochemical assays. Furthermore, specialized flow cytometry, such as eosin-5-maleimide (EMA) binding, remains critical for the diagnosis of red cell membrane defects. Therapeutic management is also undergoing a transformation. Beyond traditional supportive care and hematopoietic stem cell transplantation (HSCT), groundbreaking gene-editing therapies, most notably CRISPR/Cas9-mediated BCL11A enhancer editing, offer the potential for curative outcomes in beta-hemoglobinopathies. Novel pharmacological agents, such as luspatercept for thalassemia and mitapivat for pyruvate kinase deficiency, are providing targeted options to improve erythropoiesis and reduce transfusion burden. Despite these advances, challenges remain in ensuring equitable access to these high-cost interventions and addressing the diagnostic gaps in resource-limited settings.