ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
28690296 In 2017, Xu et al. used PCR-sequencing on 210 unrelated patients with sporadic cases of dilated cardiomyopathy (DCM) to identify potential variants in NKX2-5. 1 patient was found to have a novel, confirmed de novo nonsense variant in NKX2-5. In addition to DCM, this patient also had progressive atrioventricular block (AVB).
26679770 In 2016, Elles?e et al. used PCR on 39 Danish individuals with familial congenital heart defect (CHD) to identify potential variants in NKX2-5. Upon sequencing the PCR products, a frameshift variant resulting in a truncated protein product was identified in 1 individual with atrial septal defect (ASD). Additionally, this variant was identified in 4 other family members with ASD and other phenotypes including atrioventricular block (AVB). As a note, 1 family member had a variety of heart defects including ASD, AVB, coarctation of aorta (CoA), persistent left superior vena cava (PLSVC), and double outlet right ventricle fallout type (DORV-TOF) but died at 8 months of age and never received genetic testing. Further, 1 healthy family member was found to be a carrier of this NKX2-5 variant but had never had an echocardiogram performed.
17891520 In 2007, Pabst et al. used PCR on 5 family members who the authors describe as, ?affected by autosomal-dominant inherited atrioventricular (AV) conduction block with atrial septal defects (ASD) and other congenital cardiovascular diseases (CCVD)? to identify variants in NKX2-5. Analysis revealed that all 5 affected individuals had a novel variant in NKX2-5 resulting in a premature stop codon. Of note, this variant was absent in the 3 healthy family members who were tested.

Haploinsufficiency phenotype comments:

There have been reports of larger deletions involving NKX2-5 (as well as other genes that suggest that NKX2-5) could be causative of cardiovascular disorders (PMIDs: 16470726, 31654754). However, there is little evidence demonstrating loss of function of NKX2-5 alone in association with these disorders (see above). For this reason, the HI score is currently 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity