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The association between ZFPM2 and Tetralogy of Fallot is supported by four unrelated probands with heterozygous missense variants in ZFPM2 ([PMID:21919901]; [PMID:28372585]). Functional assays—including co-immunoprecipitation, luciferase reporter assays, and zebrafish embryo modeling—demonstrate that these variants impair ZFPM2 interaction with GATA4 and lead to cardiac outflow tract malformations. Based on ClinGen criteria, this evidence meets a Moderate level of clinical validity due to multiple probands and concordant experimental data.
Tetralogy of Fallot arises in a heterozygous autosomal dominant context with reduced penetrance. Sequencing of 95 TOF patients identified c.2209A>G (p.Lys737Glu) in a conserved zinc-finger domain of ZFPM2 ([PMID:21919901]). Further target exome sequencing in 106 TOF patients revealed an additional deleterious ZFPM2 variant, reinforcing the variant spectrum to include rare missense changes affecting protein function.
No familial segregation data are available for ZFPM2 variants in TOF, consistent with mostly sporadic case presentations.
In HEK293T cells, ZFPM2 missense mutants show significantly reduced binding to GATA4 and enhanced inhibition of GATA4-driven transcriptional activity. In zebrafish embryos, injection of mutant ZFPM2 mRNA leads to increased incidence of abnormal cardiac chamber morphology and disrupted left-right asymmetry by 72 hpf, mirroring key features of Tetralogy of Fallot ([PMID:28372585]).
Heterozygous ZFPM2 missense variants have been identified in multiple unrelated TOF probands and shown to disrupt a critical transcriptional co-regulator interaction in cardiac development. While segregation data are lacking, the combination of genetic findings and robust functional evidence supports a Moderate gene–disease association under ClinGen standards. Key Take-home: ZFPM2 variant screening should be included in the diagnostic evaluation of Tetralogy of Fallot due to clear mechanistic insight and clinical relevance.
Gene–Disease AssociationModerate4 unrelated probands with ZFPM2 variants in TOF; concordant functional data Genetic EvidenceModerate4 probands with heterozygous ZFPM2 missense variants in TOF; no segregation data Functional EvidenceModerateHEK293T CO-IP and luciferase assays plus zebrafish model show disrupted ZFPM2-GATA4 interaction and cardiac defects |