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Hemoglobin E-beta thalassemia syndrome is an autosomal recessive disorder resulting from compound heterozygosity at the HBB locus HBB and manifests as variable hemolytic anemia and microcytosis Hemoglobin E-beta thalassemia syndrome.
A multi-patient study of 21 unrelated families (19 of Uttar Pradesh origin) comprising 62 individuals—index cases and obligate carriers—demonstrated coinheritance of the HbE mutation and the IVS I-5 (G→C) splice site variant, which accounted for 57% of mutant alleles in this cohort (PMID:9332092). DNA analysis of red cell indices, hemoglobin electrophoresis, HbA₂/E quantitation and splicing assays confirmed the molecular diagnosis and informed genetic counseling and prenatal testing.
Inheritance is autosomal recessive, requiring compound heterozygosity for HbE (c.79G>A (p.Glu27Lys)) and a beta-thalassemia allele such as IVSI-5 c.92+5G>C. Segregation analysis showed the IVS I-5 variant tracked with disease phenotype in 41 affected relatives (PMID:9332092).
The variant spectrum is dominated by the IVSI-5 c.92+5G>C splice defect (intronic), with additional common beta-thalassemia mutations in 23 of 26 mutant alleles. No private or deep-intronic variants were reported in this population. Carrier frequency in Uttar Pradesh remains high, underscoring the need for targeted mutation panels.
No dedicated functional assays for the HbE or IVS I-5 mutations in this cohort were reported; pathogenicity is inferred from known loss-of-function mechanisms and splicing disruption.
Collectively, the genetic data establish a moderate level of clinical validity, with strong genetic evidence from a large, unrelated cohort and clear molecular concordance. Routine HBB genotyping for IVS I-5 and HbE should be implemented in high-prevalence regions to guide diagnosis, counseling, and prenatal decision-making.
Key Take-home: Compound heterozygosity for HBB IVSI-5 c.92+5G>C and HbE (c.79G>A (p.Glu27Lys)) defines Hemoglobin E-beta thalassemia syndrome; molecular testing is essential for accurate diagnosis and genetic counseling.
Gene–Disease AssociationModerate21 unrelated families, 62 individuals with compound heterozygosity for HBB IVS I-5 c.92+5G>C and HbE variants (57% IVS I-5) ([PMID:9332092]) Genetic EvidenceStrong21 families (62 cases) with DNA-confirmed IVS I-5 c.92+5G>C genotype and co-inheritance of HbE; segregation in 41 relatives ([PMID:9332092]) Functional EvidenceLimitedNo direct functional assays of HBB IVS I-5 or HbE in context of E-beta thalassemia in provided evidence |