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Hereditary elliptocytosis (HE) is an inherited hemolytic anemia characterized by elliptical erythrocytes due to defects in the red blood cell membrane skeleton. EPB41 encodes protein 4.1R, a critical adapter stabilizing spectrin–actin associations. Loss-of-function variants in EPB41 disrupt membrane integrity, leading to mechanical instability and chronic hemolysis. HE exhibits autosomal dominant inheritance and is confirmed by characteristic peripheral smear morphology and genetic testing. Multiple independent cohorts have reported truncating EPB41 alleles, firmly establishing gene-disease causality. Genetic diagnosis guides clinical management and family counseling.
In a multi-patient sequencing study of 15 individuals with HE or hereditary pyropoikilocytosis, five unrelated probands harbored heterozygous nonsense EPB41 variants (c.993C>A (p.Tyr331Ter), c.820C>T (p.Gln274Ter), c.1301G>A (p.Trp434Ter), c.1522C>T (p.Arg508Ter), c.1660C>T (p.Arg554Ter)) (PMID:27667160). All alleles were absent from population databases and predicted to undergo nonsense-mediated decay. These truncating variants co-segregated with HE in available family data and underpin a loss-of-function mechanism. The variant spectrum highlights multiple independent LoF alleles across distinct exons. This series provides robust case-level genetic evidence for EPB41 in HE.
A case report described an 89-year-old Korean patient with cholelithiasis (HP:0001081) and pancreatitis (HP:0001733) presenting with ~60% elliptocytes on smear. Targeted panel sequencing identified a novel heterozygous EPB41 c.2112G>A (p.Trp704Ter) variant absent in control databases and confirmed by Sanger sequencing (PMID:32807033). The same nonsense allele recurred in two unrelated hereditary elliptocytosis cases in a separate diagnostic panel of four patients (PMID:36832257). Recurrence of c.2112G>A in independent families bolsters pathogenicity. Phenotypic heterogeneity included gallstones and acute pancreatitis, underscoring clinical variability.
All EPB41 variants demonstrate autosomal dominant transmission with evidence of co-segregation in small pedigrees. No large multigenerational segregation studies have been reported, and no conflicting evidence has emerged to dispute EPB41 involvement in HE. Allele frequencies in gnomAD are negligible, supporting rarity. The collective genetic data satisfy ClinGen criteria for moderate clinical validity based on multiple independent case-level LoF findings. Further segregation and larger family studies would strengthen the genetic framework.
Functional assays reveal that EPB41 exon 16 inclusion is regulated by the RNA binding protein RBM38 during erythroid differentiation. In vitro minigene splicing experiments demonstrated robust RBM38-dependent activation of EPB41 exon 16 (PMID:24250749). Truncating variants are predicted to abolish 4.1R expression, destabilizing spectrin–actin networks. While no animal models of EPB41-related HE have been described, cellular data confirm loss of structural integrity. Experimental evidence provides coherent mechanistic support but remains limited in scope.
Together, heterozygous truncating variants in EPB41 are established causes of autosomal dominant hereditary elliptocytosis. The convergence of five distinct nonsense alleles, recurrence of p.Trp704Ter, and functional splicing data support a moderate ClinGen classification. EPB41 should be included in HE diagnostic panels to enable precise molecular diagnosis and inform prognosis and counseling. Key take-home: EPB41 truncating variants confer a clinically actionable form of autosomal dominant HE.
Gene–Disease AssociationModerateEight unrelated probands with heterozygous truncating EPB41 variants, including five distinct alleles in a multi-patient cohort (PMID:27667160), one index case (PMID:32807033) and recurrence in two panel-screened cases (PMID:36832257) Genetic EvidenceModerateMultiple independent case-level truncating EPB41 variants in >8 probands across distinct studies; loss-of-function mechanism established Functional EvidenceLimitedIn vitro splicing assays and predicted loss-of-function effects support pathogenic mechanism but lack animal models |