HSPA9 – Autosomal Recessive Sideroblastic Anemia

HSPA9 encodes the mitochondrial chaperone mortalin, which partners with HSCB and GLRX5 to transfer 2Fe-2S clusters critical for erythroid hemoglobinization. In a cohort of 41 genomically tested anemic individuals, biallelic pathogenic HSPA9 variants were identified in 2 unrelated probands with congenital sideroblastic anemia under an autosomal recessive model (PMID:38360212). These patients presented with early‐onset microcytic anemia and ring sideroblasts; no additional familial segregation data were reported.

Functional studies of patient‐derived cells demonstrated impaired Fe-S cluster biogenesis, defective mitochondrial iron utilization, and reduced hemoglobinization that were rescued by wild-type HSPA9 complementation, supporting a loss-of-function mechanism (PMID:38360212). While the experimental validation confirms pathogenicity in vitro, the genetic evidence is limited to two cases without segregation or broader cohort replication. Further multi‐family studies are needed to establish penetrance and expand the allelic series.

Key Take-home: HSPA9 should be included in gene panels for congenital sideroblastic anemia, with AR inheritance and functional assays guiding variant interpretation.

References

• The Journal of molecular diagnostics • 2024 • Comprehensive Genomic Analysis Identifies a Diverse Landscape of Sideroblastic and Nonsideroblastic Iron-Related Anemias with Novel and Pathogenic Variants in an Iron-Deficient Endemic Setting PMID:38360212

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