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Kruppel-like factor 2 (KLF2) has been implicated in rare familial pulmonary arterial hypertension (PAH) based on a single heterozygous premature termination variant, c.951dup (p.Glu318ArgfsTer), disrupting the zinc-finger domain in one family with immune dysregulation but no PAH phenotype (PMID:36466816). No pathogenic KLF2 variants have been identified in large PAH gene-panel screenings of over 300 consecutive patients, and there is no evidence of segregation of PAH with KLF2 variants.
Functional assays in immune cells show that the KLF2 p.Glu318ArgfsTer variant reduces protein levels, impairs nuclear localization, and alters target gene expression, yet no vascular or pulmonary-specific functional studies have demonstrated a direct mechanism linking KLF2 deficiency to PAH. Current evidence is limited and insufficient for clinical or diagnostic application of KLF2 in PAH. Additional cohorts and functional studies focused on pulmonary vascular biology are required.
Gene–Disease AssociationLimitedSingle family with heterozygous KLF2 truncating variant lacking PAH phenotype; no replication in PAH cohorts Genetic EvidenceLimitedNo KLF2 variants identified in >300 PAH patients; only one family report without PAH Functional EvidenceLimitedImmunological functional data exist but no pulmonary vascular assays linking KLF2 variants to PAH |