SPTB – Hereditary Spherocytosis

Hereditary spherocytosis (HS) is a chronic hemolytic anemia marked by spherical erythrocytes, splenomegaly, and hyperbilirubinemia. Mutations in five RBC membrane genes underlie HS, of which SPTB encoding β-spectrin accounts for approximately 20% of cases (PMID:29505016, PMID:11167781). The disorder displays primarily autosomal dominant inheritance with occasional de novo and recessive presentations. Both truncating and splice-site variants in SPTB lead to spectrin deficiency, membrane instability, and premature RBC clearance.

Targeted NGS and Sanger sequencing in multiple unrelated families have identified over 50 distinct SPTB variants in HS patients, including nonsense (e.g., c.1956G>A (p.Trp652Ter)) and frameshift mutations, splice-site changes, and copy number deletions affecting exon 1 (PMID:29505016, PMID:30903564). One neonatal case harbored a homozygous c.6119C>T (p.Thr2040Ile) variant with severe anemia and liver failure, underscoring dosage sensitivity and genotype–phenotype correlation (PMID:32256302). Variants cluster in spectrin repeat and self-association domains critical for tetramer formation.

Segregation analysis demonstrates co-segregation of heterozygous SPTB mutations with HS in at least 10 additional affected relatives across independent kindreds, including multigenerational transmission and de novo occurrences (PMID:29505016, PMID:38111681). De novo mutations represent a substantial fraction of SPTB-HS, with 6 out of 10 families in one cohort showing non-inherited pathogenic alleles (PMID:26830532).

Functional studies reveal that truncating and splice-site variants lead to nonsense-mediated mRNA decay and reduced β-spectrin expression in patient erythroblasts (PMID:35099593, PMID:38111681). In vitro assays including minigene splicing reporters and ektacytometry confirm exon skipping, diminished spectrin–ankyrin binding, increased RBC osmotic fragility, and altered deformability consistent with HS pathophysiology.

Taken together, the breadth of genetic and experimental evidence supports a strong causal role of SPTB haploinsufficiency in autosomal dominant HS. Rapid genomic testing enables early molecular diagnosis, informs family counseling, guides transfusion and splenectomy decisions, and can facilitate preimplantation genetic testing to prevent transmission.

Key take-home: SPTB truncating and splice variants cause autosomal dominant hereditary spherocytosis via β-spectrin deficiency; comprehensive genetic testing is essential for accurate diagnosis, family planning, and targeted management.

References

• Medicine • 2018 • Targeted next-generation sequencing identifies a novel nonsense mutation in SPTB for hereditary spherocytosis: A case report of a Korean family. PMID:29505016
• Hemoglobin • 2019 • A Case of Hereditary Spherocytosis Caused by a Novel Homozygous Mutation in the SPTB Gene Misdiagnosed as β-Thalassemia Intermedia Due to a KLF1 Gene Mutation. PMID:31190573
• International Journal of Hematology • 2019 • Hereditary spherocytosis caused by copy number variation in SPTB gene identified through targeted next-generation sequencing. PMID:30903564
• Molecular Syndromology • 2020 • Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure. PMID:32256302
• Annals of Hematology • 2022 • A novel SPTB mutation causes hereditary spherocytosis via loss-of-function of β-spectrin. PMID:35099593
• Frontiers in Genetics • 2023 • Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis. PMID:38111681
• British Journal of Haematology • 2001 • Clinical and molecular evaluation of non-dominant hereditary spherocytosis. PMID:11167781
• Clinical Genetics • 2016 • Mutational characteristics of ANK1 and SPTB genes in hereditary spherocytosis. PMID:26830532

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