NFATC1 – Congenital Heart Disease

The nuclear factor of activated T cells cytoplasmic 1 (NFATC1) is a calcium-dependent transcription factor essential for valvular and septal morphogenesis during cardiac development. Knock‐out and lineage‐tracing studies in mice have established NFATC1 as a driver of endocardial cushion formation and valve primordia specification (HP:0001671).

Genetic evidence for NFATC1 in congenital heart disease comes from multiple independent probands. In a cohort of 22 patients with isolated atrioventricular septal defect (AVSD) and 38 with AVSD plus heterotaxy, three heterozygous missense variants—c.628G>A (p.Val210Met), c.1100C>T (p.Ala367Val), and c.2086G>A (p.Ala696Thr)—were identified, each disrupting NFATC1 nuclear translocation and transactivation and causing cardiac looping defects in zebrafish ([PMID:30007050]). Additionally, in a Chinese family with fatal tricuspid atresia, a de novo c.964G>A (p.Asp322Asn) variant reduced NFATC1 protein stability and downstream DEGS1 expression in vitro ([PMID:34363434]). Together, these reports describe 4 unrelated probands with heterozygous NFATC1 missense alleles inherited in an autosomal dominant fashion.

Functional assays demonstrate that NFATC1 mutants show defective calcineurin‐mediated dephosphorylation, impaired nuclear localization, and reduced reporter activity in mammalian cells. In zebrafish, expression of patient-derived alleles phenocopied human AVSD and septal defects, confirming pathogenicity. These findings are concordant with the known requirement of NFATC1 in valve cushion EMT and chamber septation.

No large population studies have refuted the association, and no common variants in NFATC1 have shown genome-wide association with CHD in control cohorts. The allelic spectrum—heterozygous missense changes—points to a dominant-negative or haploinsufficient mechanism.

In summary, NFATC1 meets a Moderate ClinGen clinical validity classification for congenital heart disease based on multiple unrelated probands, segregation of heterozygous missense variants, and concordant in vitro and in vivo functional data. NFATC1 genetic testing can inform molecular diagnosis and risk stratification in CHD.

Key Take-home: Heterozygous NFATC1 missense variants cause septal and valvular defects via impaired transcriptional activation and nuclear localization, supporting its use in genetic diagnosis of congenital heart disease.

References

• Human Mutation • 2018 • Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect. PMID:30007050
• Molecular Genetics & Genomic Medicine • 2021 • Genetic and functional analyses detect one pathological NFATC1 mutation in a Chinese tricuspid atresia family. PMID:34363434

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