• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
NKX2-5 (HGNC:2488) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
NK2 homeobox 5
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
CSX, NKX2E
Alias symbols
CSX1, NKX2.5, NKX4-1
%HI
9.67(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.95(Read more about gnomAD pLI score)
LOEUF
0.33(Read more about gnomAD LOEUF score)
Cytoband
5q34
Genomic Coordinates
GRCh37/hg19: chr5:172659112-172662209 NCBI Ensembl UCSC
GRCh38/hg38: chr5:173232109-173235206 NCBI Ensembl UCSC
MANE Select Transcript
NM_004387.4 ENST00000329198.5 (Read more about MANE Select)
Function
Transcription factor required for the development of the heart and the spleen (PubMed:22560297). During heart development, acts as a transcriptional activator of NPPA/ANF in cooperation with GATA4 (By similarity). May cooperate with TBX2 to negatively modulate expression of NPPA/ANF in the atrioventricular canal (By similarity). Binds to the core DNA motif of NPPA promoter (PubMed:22849347, PubMed:26926761). Together with PBX1, required for spleen development through a mechanism that involves CD... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-31425
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
07/22/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 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).
  • PUBMED: 26679770
    In 2016, Ellesøe 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.
  • PUBMED: 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.
HI Evidence 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). In the 8 articles included below, there are a total of 60 examples involving loss of function variants in NKX2-5 being identified in individuals with various cardiovascular disorders. Additional articles: PMID: 16896344 In 2006, Gutierrez-Roelens et al. used single-stranded conformation polymorphism (SSCP), heteroduplex analysis and direct sequencing on a family with AV conduction disturbances. The authors identified a nonsense variant (p.Tyr256X) in all 5 affected individuals in the family. PMID: 25742962 In 2015, Hassan et al. report on 2 families with autosomal dominant atrial septal defects (ADSs). Using targeted sequencing, frameshift variants in NKX2-5 were identified. Family A had the frameshift variant p.Y241fs which was present in 10 affected family members and 1 unaffected individual. In family B, the variant p.G206fs was identified in 3 affected family members and none of the unaffected family members tested. PMID: 10943630 In 1999, Hosoda et al. used reported on an individual with atrial septal defect (ASD). Per the authors, "Sequence analysis revealed a C to T transversion at nucleotide 701 in one allele (Fig3), resulting in the production of a carboxy-terminal truncated protein due to the nonsense mutation at amino acid 198." Of note, the proband also had a deceased father who had died suddenly and a deceased son who was affected by ASD. PMID: 10587520 In 1999, Benson et al. described 5 variants (4 nonsense variants and 1 splice site variant) in NKX2-5 present in 21 affected individuals. PMID: 9651244 In 1998, Schott et al. described 2 families with atrial septal defect (ASD). The authors identified truncating variants in both families present in a total of 7 affected individuals. PMID: 15689439 In 2005, Sarkozy et al. described a group of 13 unrelated sporadic cases and 16 families with atrial septal defect (ASD). Analysis investigated NKX2-5 and GATA4. The authors report of 1 confirmed de novo frameshift variant in an affected individual, as well as another frameshift variant in a different proband and 2 affected family members. PMID: 12414819 In 2002, Watanabe et al. used PCR on 2 families with congenital heart disease and AV block. The authors identified frameshift variants in NKX2-5 resulting in truncated protein products in both families. There were a total of 5 affected individuals with the NKX2-5 variants. PMID: 15810002 In 2005, Hirayama-Yamada et al. used PCR on 16 families with atrial septal defect (ASD) to identify potential variants in NKX2-5 and GATA4. The authors identified a frameshift variant in NKX2-5 ( A88Xfs) in 1 family, with a total of 4 affected individuals harboring the variant.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)