NKX2-5 – Dilated Cardiomyopathy

Heterozygous NKX2-5 variants have been identified in autosomal-dominant dilated cardiomyopathy (DCM) patients, implicating impaired cardiac transcriptional regulation as a pathogenic mechanism. A 2019 case report first described a young man with out-of-hospital sudden cardiac arrest who harbored a de novo c.809G>A (p.Cys270Tyr) NKX2-5 variant and was diagnosed with early-stage DCM ([PMID:30611920]). Subsequent sequencing of 210 unrelated sporadic adult-onset DCM patients revealed two additional heterozygous missense variants, c.415A>T (p.Arg139Trp) and c.416G>A (p.Arg139Lys), each absent in 600 reference chromosomes and affecting evolutionarily conserved residues ([PMID:28690296]). In an Icelandic genome-wide study of 424 DCM cases versus 337,689 controls, a recurrent c.435C>G (p.Phe145Leu) variant was enriched among affected individuals and associated with heart failure and sudden cardiac death ([PMID:30354339]).

Inheritance is autosomal dominant with no reported multi-generation segregation data. Three unrelated probands carry distinct NKX2-5 missense alleles in DCM, supporting a Limited level of genetic evidence. Functional assays of p.Arg139Trp demonstrate significantly reduced transcriptional activity in dual-luciferase reporter systems and loss of synergistic activation with GATA4 and TBX20, consistent with a haploinsufficiency mechanism.

References

• Journal of Electrocardiology • 2019 • Double de novo mutations in dilated cardiomyopathy with cardiac arrest. PMID:30611920
• International Heart Journal • 2017 • Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy. PMID:28690296
• Circulation: Genomic and Precision Medicine • 2018 • Variants in NKX2-5 and FLNC Cause Dilated Cardiomyopathy and Sudden Cardiac Death. PMID:30354339

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