NKX2-5 – Tetralogy of Fallot

NKX2-5 encodes a cardiac homeobox transcription factor essential for heart development. A case–control study of 150 Egyptian children with congenital heart disease, including tetralogy of Fallot, found the NKX2-5 rs2277923 CT genotype in 58% of cases versus 36% of controls and the rs28936670 AG genotype in 82% of cases, suggesting a modest risk effect (PMID:30834692). However, sequencing of fresh cardiac tissues from 38 unrelated non-syndromic tetralogy of Fallot patients revealed no somatic NKX2-5 mutations, indicating that pathogenic somatic variants are uncommon in this cohort (PMID:21519287). A heterozygous missense change c.73C>T (p.Arg25Cys) was identified in a single tetralogy of Fallot proband but also found in healthy relatives and controls, challenging its role as a disease-causing allele (PMID:17891434). To date, no pathogenic germline NKX2-5 variants have been shown to segregate with tetralogy of Fallot in families, and the evidence for causality remains limited.

Functional studies support NKX2-5 haploinsufficiency as a mechanism for cardiac malformations. Nkx2-5 knockout mice exhibit embryonic lethality, ventricular and conduction system hypoplasia, and altered expression of downstream targets such as atrial natriuretic factor (PMID:11572777). Yeast-based transactivation assays of homeodomain mutants demonstrate loss-of-function and dosage sensitivity for alleles associated with septal defects (PMID:15917268). Although these data confirm NKX2-5’s critical role in cardiogenesis, direct experimental modeling of tetralogy of Fallot remains lacking. Additional case series and mechanistic insights exceed the ClinGen scoring cap. Key take-home: Common NKX2-5 variants show association with risk for tetralogy of Fallot, but definitive pathogenic alleles and familial segregation are not yet established, underscoring the need for comprehensive genetic and functional studies.

References

• Molecular genetics & genomic medicine • 2019 • Association of NKX2-5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children. PMID:30834692
• Pathology • 2011 • Investigation of somatic NKX2-5, GATA4 and HAND1 mutations in patients with tetralogy of Fallot. PMID:21519287
• Pediatric cardiology • 2008 • The effect of p.Arg25Cys alteration in NKX2-5 on conotruncal heart anomalies: mutation or polymorphism? PMID:17891434
• Cell • 2001 • A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. PMID:11572777
• Human molecular genetics • 2005 • Functional dissection of sequence-specific NKX2-5 DNA binding domain mutations associated with human heart septation defects using a yeast-based system. PMID:15917268

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