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

Abstract

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.

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

“…The well-established environmental factors underlying CHD include maternal conditions (such as innutrition, viral infection and endocrine disorder) and exposures to toxic chemicals, therapeutic drugs, or ionizing radiation during pregnancy (Patel and Burns, 2013). However, increasing studies underscore the genetic defects underpinning CHD, and variations in over 70 genes, encompassing those encoding transcription factors, signaling molecules, and sarcomeric proteins, have been involved in CHD (Bashamboo et al, 2018;Cantù et al, 2018;Jaouadi et al, 2018;Li et al, 2018a,c;Lombardo et al, 2018;Manheimer et al, 2018;Pierpont et al, 2018;Razmara and Garshasbi, 2018;Stephen et al, 2018;Xu et al, 2018;Yu Z et al, 2018;Alankarage et al, 2019;Gao et al, 2019;Kalayinia et al, 2019Kalayinia et al, , 2020Ma et al, 2019;Wang J et al, 2019, Wang Z et al, 2019Watkins et al, 2019;Zhu et al, 2019;Faucherre et al, 2020;Shabana et al, 2020;Zhao et al, 2020). Among the recognized CHD-causative genes, the majority code for cardiac transcription factors, encompassing TBX5, GATA4, and NKX2-5 (Li and Yang, 2017).…”

Prevalence of Structural Heart Diseases Detected by Handheld Echocardiographic Device in School-Age Children in Iran: The SHED LIGHT Study

“…Several factors predispose individuals to a higher risk of disease development, particularly pathologies with a genetic background [ 25 ]. Some studies have emphasized the role of genes in the causation of CHD and cardiomyopathy [ 5 26 ], and recommended against inbreeding and consanguineous marriage, particularly in developing countries [ 26 ].…”

A Phenotype and Genotype Case Report of a Neonate With Congenital Bilateral Coronary Artery Fistulas and Multiple Collateral Arteries

“…A specific gene with different variants may result in different phenotypes. For example, different variants in NOTCH1 have been observed in several types of CHD, such as pulmonary stenosis (PS) ( 30 ), left ventricular outflow tract obstructive ( 31 ), and ventricular septal defect ( 32 ). Taken together, the compound heterozygous variants, c.T470G (p. L157R), and c.A1622G (p. D541G), in DRC1 is the most probable cause of CHD in the patient.…”