ClinGen Dosage Sensitivity Curation Page
NKX2-5
- Curation Status: Complete
- id: ISCA-31425
- Date last evaluated: 2020-06-24
- Issue Type: ClinGen Gene Curation
- Gene type: protein-coding
- ClinGen: Search for information about NKX2-5 at clinicalgenome.org
- Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/1482
- OMIM: https://omim.org/entry/600584
- ClinGen Haploinsufficiency Score: 1
- ClinGen Triplosensitivity Score: 0
- ExAC pLI score: 0.95
Select assembly:
(NC_000005.9)
(NC_000005.10)
- Haploinsufficiency score: 1
- Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
| 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