Beta-thalassemia HBB/LCRB is a hereditary hemoglobin disorder arising from absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain), encoded by the HBB gene on chromosome 11. According to GeneReviews (Beta-Thalassemia, NCBI Bookshelf), the condition encompasses two clinically significant forms: beta-thalassemia major, characterized by severe transfusion-dependent anemia, and beta-thalassemia intermedia, defined by milder anemia that does not require regular red blood cell transfusions from early childhood. Three recognized subtypes are documented in this packet: beta-thalassemia major, beta-thalassemia intermedia, and thalassemia minor. The ClinGen Gene Curation Expert Panel has classified HBB as DEFINITIVELY causative of this condition. GeneReviews reports elevated prevalence in populations from the Mediterranean, the Middle East, Central and Southeast Asia, and the Indian subcontinent, with the highest incidences recorded in Cyprus (14%), Sardinia (12%), and Southeast Asia. The condition is listed as a rare disease by Orphanet and GARD (NIH).

Per GeneReviews, beta-thalassemia major typically comes to medical attention before age two years. Clinical findings at presentation include pallor, poor weight gain, stunted growth, mild jaundice, and hepatosplenomegaly. Laboratory findings include reduced or absent hemoglobin A (HbA) on newborn screening. In the major form, the near-complete absence of functional beta globin produces severe hemolytic anemia; without regular red blood cell transfusions the condition is life-threatening. Beta-thalassemia intermedia presents with a more variable clinical course: residual beta globin synthesis results in milder anemia with a later and more heterogeneous age of presentation. GeneReviews genotype-phenotype data indicate that clinical severity is determined by the extent of alpha/non-alpha globin chain imbalance. Non-assembled alpha globin chains precipitate within erythroid precursors as intracellular inclusions, damaging those cells and shortening red blood cell survival in both the bone marrow and the peripheral circulation. Phenotype-level HPO terms were not available in this packet; the symptom description above derives from certified GeneReviews content.

Beta-thalassemia HBB/LCRB results from pathogenic variants in the HBB gene located on chromosome 11. The ClinGen Gene Curation Expert Panel has established DEFINITIVE evidence for the HBB-beta-thalassemia gene-disease relationship. Per GeneReviews, the disorder arises when mutations cause absent (beta-zero thalassemia) or reduced (beta-plus thalassemia) synthesis of the hemoglobin beta subunit, disrupting the stoichiometric balance between alpha globin and non-alpha globin chains. The unbalanced chain synthesis drives the pathological cascade of erythroid precursor damage and ineffective erythropoiesis. Inheritance pattern data were not certified in this packet; GeneReviews' genetic counseling section notes that the mode of inheritance is relevant to familial risk assessment.

GeneReviews identifies the following as suggestive clinical and laboratory findings that prompt further evaluation for beta-thalassemia major: pallor, poor weight gain, stunted growth, mild jaundice, and hepatosplenomegaly appearing in infants or children under two years of age, combined with reduced or absent hemoglobin A on newborn screening. GeneReviews describes differential diagnoses to consider, including beta-thalassemia associated with additional hematologic or non-hematologic features, which in rare instances may have distinct molecular etiologies. Molecular genetic testing of the HBB gene is a component of the diagnostic workup as described in the GeneReviews chapter. Comprehensive management guidelines, including post-diagnosis evaluations, have been published by the Thalassemia International Federation, per GeneReviews.

The FDA-approved treatment listed in this packet for beta-thalassemia HBB/LCRB is Casgevy (exagamglogene autotemcel; BLA approval December 8, 2023; market status ACTIVE). GeneReviews describes hematopoietic stem cell transplant (HSCT) as a targeted therapy that, when successful, can eliminate transfusion dependence and reduce iron burden in individuals with beta-thalassemia major. GeneReviews also identifies agents and circumstances associated with adverse outcomes in the context of this condition: alcohol consumption (noted to have a synergistic effect with iron-induced liver damage in those with liver disease), iron-containing preparations, and exposure to infection. No patient-specific dosing, treatment sequencing, or clinical guidance is derived from this packet. GeneReviews notes that comprehensive management recommendations are available through the Thalassemia International Federation.

Certified natural history data were not available in this packet. Per GeneReviews, individuals with beta-thalassemia major require regular red blood cell transfusions to survive in the absence of definitive intervention such as HSCT. Beta-thalassemia intermedia is associated with a more variable clinical course given its milder anemia, with later and more heterogeneous disease presentation. GeneReviews notes that the long-term outlook is strongly influenced by access to transfusion support, iron chelation, and, where applicable, hematopoietic stem cell transplantation. Beyond these characterizations from GeneReviews, prognosis data certified to this specific MONDO entity were not available in this packet.

The research landscape digest for beta-thalassemia HBB/LCRB encompasses 243 classified publications, including 71 reviews and 18 case reports, with representation across gene therapy and biomarker research areas and recent trial-linked publications, per internal Kisho classification. ClinicalTrials.gov records 50 active trials indexed to this condition. Active recruiting studies include a Phase 2/3 study investigating the efficacy, pharmacokinetics, and safety of mitapivat in pediatric participants with transfusion-dependent alpha- or beta-thalassemia (NCT07506863) and a study on the same agent in a broader thalassemia population (NCT07517133), both recruiting per ClinicalTrials.gov. GeneReviews identifies investigational therapeutic strategies targeting iron dysregulation, including minihepcidin, TMPRSS6 inhibitors, and ferroportin inhibitors, with initial clinical trials ongoing. Etavopivat, a pyruvate kinase activator, is noted in GeneReviews as under evaluation in a Phase III clinical trial for both transfusion-dependent and non-transfusion-dependent thalassemia.