A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non-syndromic congenital heart disease


Kalayinia S, Maleki M, Mahdavi M, Mahdieh N.

J Clin Lab Anal. 2020 Apr;34(4):e23147. doi: 10.1002/jcla.23147. Epub 2019 Dec 22.

PMID: 31867804 Free PMC Article

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Background: Congenital heart disease (CHD) is the most common birth defect which can arises from different genetic defects. The genetic heterogeneity of this disease leads to restricted success in candidate genes screening method. Emerging approaches such as next-generation sequencing (NGS)-based genetic analysis might provide a better understating of CHD etiology in the patients who are left undiagnosed. To this aim, in this study, we survived the causes of CHD in an Iranian family who was consanguineous and had two affected children.

Methods: Affected individuals of this family were checked previously by PCR-direct sequencing for six candidate genes (NKX2-5, ZIC3, NODAL, FOXH1, GJA1, GATA4) and had not revealed any reported CHD causative mutations. Whole-exome sequencing (WES) was performed on this family probond to determine the underlying cause of CHD, and the identified variants were confirmed and segregated by Sanger sequencing.

Results: We identified one heterozygous missense mutation, c.T6797C (p.Phe2266Ser), in the NOTCH1 gene, which seems to be the most probably disease causing of this family patients. This mutation was found to be novel and not reported on 1000 Genomes Project, dbSNP, and ExAC.

Conclusion: Worldwide, mutations in NOTCH1 gene are considered as one of the most known causes of CHD. The found NOTCH1 variant in this family affected individuals was the first report from Iran. Yet again, this result indicates the importance of NOTCH1 screening in CHD patients.


Figure 1 Genetic and protein changes of NOTCH1. A, Pedigree of the family. B, Genotypes of a novel de novo mutation c.T6797C (p.Phe2266Ser) detected in both affected children, and parents had normal genotypes (C) Schematic of NOTCH1 protein domains (up) displays epidermal growth factor (EGF), Lin/Notch repeat (LNR), heterodimerization domain (HD), transmembrane domain (TD), RBPJ‐associated molecule domain (RAM), ankyrin repeat (ANK), transactivation domain (TAD), and PEST domain (PEST). Multiple sequence alignment of the NOTCH1 protein sequences (down) indicates the Phe2266 residue is highly conserved among species. D, The echocardiograms of affected family members, ventricular septal defect (left) and patent ductus arteriosus (right). Ao, aorta; LA, left atrium; LPA, left pulmonary artery; RV, right ventricle