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This summary evaluates the association between SFXN4 and macrocytic anemia (MONDO_0002281). Biallelic mutations in SFXN4, including a truncating variant c.668del (p.Lys223fs) identified in two probands (PMID:24119684), have been reported in patients presenting with mitochondrial dysfunction and macrocytic anemia. The genetic evidence, albeit based on a limited number of cases, shows that these loss‑of‑function mutations are consistent with an autosomal recessive inheritance pattern. The variant spectrum encompasses frameshift and splicing alterations that likely disrupt protein function, supporting a causative role in the disease phenotype. Although segregation data from additional family members is minimal, the repeated identification of similar deleterious variants underscores a pathogenic mechanism involving impaired mitochondrial respiratory homeostasis and defective erythropoiesis. This genetic finding is consequential for diagnostic decision‑making and clinical management.
Functional studies further bolster the gene‑disease link by demonstrating that SFXN4 knockout or knockdown results in impaired Fe‑S cluster biogenesis, altered mitochondrial respiration, and abnormal heme biosynthesis (PMID:31873120). These experiments, performed in zebrafish models and patient fibroblasts, corroborate the biological plausibility of SFXN4 mutations leading to macrocytic anemia. The observed biochemical perturbations align with the clinical manifestations of anemia with megaloblastic features in the most severe cases. Although the current evidence is derived from only two probands, the complementary nature of genetic and functional data supports a significant, albeit limited, association. Key take‑home sentence: SFXN4 mutations warrant clinical consideration in patients with macrocytic anemia due to their demonstrable impact on mitochondrial function and heme synthesis.
Gene–Disease AssociationLimitedAssociation based on identification of biallelic mutations in 2 probands (PMID:24119684) with macrocytic anemia, supported by independent functional studies (PMID:31873120). Genetic EvidenceLimitedGenetic evidence is derived from 2 probands harboring truncating mutations including c.668del (p.Lys223fs) that disrupt SFXN4 function (PMID:24119684). Functional EvidenceModerateFunctional assays in zebrafish and patient fibroblasts demonstrated impaired Fe‑S cluster formation, mitochondrial respiration, and heme biosynthesis, which mechanistically underpin the macrocytic anemia phenotype (PMID:31873120). |