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A causal link between SOX4 and familial Atrial fibrillation was identified in a four-generation Han Chinese pedigree and validated in a cohort of 196 unrelated AF patients and 278 controls. Two novel heterozygous stop-gain variants, c.211C>T (p.Gln71Ter) and c.290G>A (p.Trp97Ter), were observed to segregate with AF in the family and recurred in one additional patient, absent in controls, totaling two probands (PMID:39518344). Segregation analysis demonstrated co-inheritance of the family variant in at least five affected relatives. These findings provide limited but notable genetic evidence for SOX4 in AF predisposition.
Functional characterization using dual-reporter assays showed that both Gln71Ter and Trp97Ter mutants abolished SOX4 transactivation of GJA1 (Cx43) and disrupted the synergistic activation of SCN5A by SOX4 and TBX5 (PMID:39518344). This loss-of-function mechanism supports haploinsufficiency as the likely pathogenic basis. Although additional large cohorts are needed to strengthen genetic evidence, current data suggest SOX4 screening may inform early diagnosis and targeted management of familial AF.
Gene–Disease AssociationLimitedTwo probands with heterozygous stop-gain SOX4 variants segregating in a four-generation family and one unrelated patient; supportive but below ClinGen genetic threshold Genetic EvidenceLimitedHeterozygous loss-of-function variants identified in one pedigree (five affected relatives) and one additional case; controls negative Functional EvidenceModerateDual-reporter assays demonstrate loss of SOX4 transactivation on GJA1 and disrupted SOX4–TBX5 synergy on SCN5A |