NKX2-5

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient 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). 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 score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity