Variants in NKX2-5 and FLNC Cause Dilated Cardiomyopathy and Sudden Cardiac Death

Circ Genom Precis Med. 2018 Aug;11(8):e002151. doi: 10.1161/CIRCGEN.117.002151.


Background: Dilated cardiomyopathy (DCM) is an important cause of heart failure. Variants in >50 genes have been reported to cause DCM, but causative variants have been found in less than half of familial cases. Variants causing DCM in Iceland have not been reported before.

Methods: We performed a genome-wide association study on DCM based on whole genome sequencing. We tested the association of 32.5 million sequence variants in 424 cases and 337 689 population controls in Iceland.

Results: We identified 2 DCM variants in established cardiomyopathy genes, a missense variant p.Phe145Leu in NKX2-5 carried by 1 in 7100 Icelanders ( P=7.0×10-12) and a frameshift variant p.Phe1626Serfs*40 in FLNC carried by 1 in 3600 Icelanders ( P=2.1×10-10). Both variants associate with heart failure and sudden cardiac death. Additionally, p.Phe145Leu in NKX2-5 associates with high degree atrioventricular block and atrial septal defect ( P<1.4×10-4). The penetrance of serious heart disease among carriers of the NKX2-5 variant is high and higher than that of the FLNC variant.

Conclusions: Two rare variants in NKX2-5 and FLNC, carried by 1 in 2400 Icelanders, cause familial DCM in Iceland. These genes have recently been associated with DCM. Given the serious consequences of these variants, we suggest screening for them in individuals with DCM and their family members, with subsequent monitoring of carriers, offering early intervention.

Keywords: atrioventricular block; cardiomyopathies; genome-wide association study; heart failure; penetrance; whole genome sequencing.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cardiomyopathy, Dilated / complications*
  • Cardiomyopathy, Dilated / epidemiology
  • Cardiomyopathy, Dilated / genetics*
  • Case-Control Studies
  • Death, Sudden, Cardiac / epidemiology
  • Death, Sudden, Cardiac / etiology*
  • Female
  • Filamins / genetics*
  • Frameshift Mutation
  • Genome-Wide Association Study
  • Homeobox Protein Nkx-2.5 / genetics*
  • Humans
  • Iceland / epidemiology
  • Male
  • Middle Aged
  • Mutation, Missense
  • Penetrance
  • Young Adult


  • FLNC protein, human
  • Filamins
  • Homeobox Protein Nkx-2.5
  • NKX2-5 protein, human