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

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. © 2019 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc

Mosaic trisomy 22 in a 4-year-old boy with congenital heart disease and general hypotrophy: A case report

Background: Trisomy 22 mosaicism is a rare autosomal anomaly with survival compatibility. Recognition of the complete trisomy 22 which is incompatible with life from the mosaic form is critical for genetic counseling. Affected mosaic cases have prevalent clinical presentations such as webbed neck, developmental delay, abnormal ears, cardiac disorders, and microcephaly. Phenotype of these patients is milder than full chromosomal aneuploidy, and the severity of the phenotype depends on the count of trisomic cells. We describe a 4-year-old boy with mosaic trisomy 22 from healthy parents and no family history of any genetic disorders in the pedigree. Method and Results: The patient had determined dysmorphic clinical features including facial asymmetry, cleft palate, gastroenteritis, hydronephrosis, developmental delay, genital anomalies, dysplastic toenails, flattened nasal bridge, congenital heart defect, hearing loss, cryptorchidism, and hypotonic muscle. He is the first reported with hypothyroidism and larynx wall thickness in worldwide and the first with atrial septal defect (ASD) from Iran. Chromosomal analyses using G-banding indicated a de novo Mos 47,XY,+22(6)/46,XY(44) karyotype with no other chromosomal structural changes. Conclusions: Our observations confirm the importance of cytogenetic analyses for determining the cause of congenital anomalies and provide a useful genetic counseling. In addition, due to the fact that some of mosaic trisomy 22 features are unavoidable such as CHD and general hypotrophy, we suggest including echocardiography test for early diagnosis during the clinical assessment. © 2018 Wiley Periodicals, Inc

Is there any association between the MEF2A gene changes and coronary artery disease?

Coronary artery disease (CAD) is a common multifactorial disease with a high rate of morbidity and mortality worldwide. The MEF2A gene transcription factor belongs to the myocyte enhancer factor-2 (MEF2) family and is involved in critical processes such as calcium-dependent signaling pathways and cardiac development. Although the variants of the MEF2A gene were studied in different CAD and myocardial infarction (MI) populations, the reality of this gene association with CAD is still unclear. This study reports the first in silico investigation on MEF2A variants. All reported variants in CAD/MI patients were collected from eleven countries. Their pathogenicity and variant position conservation were surveyed by online prediction tools, including Mutation-Taster, Polyphen-2, PROVEAN, SIFT, CADD, and GERP. In silico analysis did not confirm the pathogenic effect of 21-bp deletion, which was introduced as a monogenic cause of CAD. c.704C>A (p.S235Y), c.812C>G (p.P271R), c.836C>T (p.P279L) and c.848G>A (p.G283D) missenses, c.1315C>T (p.R439X) nonsense, and seven out-of-frame deletions were predicted as disease-causing variants. Although some variants of the MEF2A gene affect protein structure, the MEF2A variation studies in CAD/MI patients and in silico analysis do not approve the association and pathogenicity of MEF2A variants in the familial/sporadic CAD. © 2020 Tehran University of Medical Sciences. All rights reserved

Next generation sequencing applications for cardiovascular disease

The Human Genome Project (HGP), as the primary sequencing of the human genome, lasted more than one decade to be completed using the traditional Sanger�s method. At present, next-generation sequencing (NGS) technology could provide the genome sequence data in hours. NGS has also decreased the expense of sequencing; therefore, nowadays it is possible to carry out both whole-genome (WGS) and whole-exome sequencing (WES) for the variations detection in patients with rare genetic diseases as well as complex disorders such as common cardiovascular diseases (CVDs). Finding new variants may contribute to establishing a risk profile for the pathology process of diseases. Here, recent applications of NGS in cardiovascular medicine are discussed; both Mendelian disorders of the cardiovascular system and complex genetic CVDs including inherited cardiomyopathy, channelopathies, stroke, coronary artery disease (CAD) and are considered. We also state some future use of NGS in clinical practice for increasing our information about the CVDs genetics and the limitations of this new technology.Key messages Traditional Sanger�s method was the mainstay for Human Genome Project (HGP); Sanger sequencing has high fidelity but is slow and costly as compared to next generation methods. Within cardiovascular medicine, NGS has been shown to be successful in identifying novel causative mutations and in the diagnosis of Mendelian diseases which are caused by a single variant in a single gene. NGS has provided the opportunity to perform parallel analysis of a great number of genes in an unbiased approach (i.e. without knowing the underlying biological mechanism) which probably contribute to advance our knowledge regarding the pathology of complex diseases such as CVD. © 2017 Informa UK Limited, trading as Taylor & Francis Group

MicroRNAs: roles in cardiovascular development and disease

Cardiovascular diseases (CVDs) comprise a group of disorders ranging from peripheral artery, coronary artery, cardiac valve, cardiac muscle, and congenital heart diseases to arrhythmias and ultimately, heart failure. For all the advances in therapeutics, CVDs are still the leading cause of mortality the world over, hence the significance of a thorough understanding of CVDs at the molecular level. Disparities in the expressions of genes and microRNAs (miRNAs) play a crucial role in the determination of the fate of cellular pathways, which ultimately affect an organism's physiology. Indeed, miRNAs serve as the regulators of gene expressions in that they perform key functions both in several important cellular pathways and in the regulation of the onset of various diseases such as CVDs. Many miRNAs are expressed in embryonic, postnatal, and adult hearts; their aberrant expression or genetic deletion is associated with abnormal cardiac cell differentiation, disruption in heart development, and cardiac dysfunction. A substantial body of evidence implicates miRNAs in CVD development and suggests them as diagnostic biomarkers and intriguing therapeutic tools. The present review provides an overview of the history, biogenesis, and processing of miRNAs, as well as their function in the development, remodeling, and diseases of the heart. © 2020 Elsevier Inc

Extracellular matrix protein 1 gene (ECM1) mutations in nine Iranian families with lipoid proteinosis

Background & objectives: Lipoid proteinosis (LP) is an autosomal recessive disease. Clinical characteristics of this disease are hoarse voice, scarring of the skin, brain calcifications, and eyelid papules (moniliform blepharosis). Mutations in the ECM1 gene on 1q21.2 are responsible for this disease. This study was conducted to investigate the mutation spectrum of ECM1 gene in nine Iranian families having at least one LP patient diagnosed clinically. Methods: The entire ECM1 gene was screened using PCR and direct sequencing in nine Iranian families with 12 suspected LP patients who were referred to the clinic, along with their parents and siblings. Thirty healthy individuals were included as controls. Results: In only one patient a homozygous G>A transition at nucleotide c.806 in exon 7 was detected. A G>A substitution at nucleotide 1243 in exon 8 that changes glycine (GGT) to serine (AGT) was observed in most of our patients. Furthermore, in one patient there was a change in the sequence of intron 8, the A>T transition in nucleotide 4307. In addition, in two cases (one patient and one healthy mother with affected child) there was a C (4249) deletion in intron 8. Interpretation & conclusions: Our results indicate that although mutation in ECM1gene is responsible for lipoid proteinosis, it is likely that this is not the only gene causing this disease and probably other genes may be involved in the pathogenesis of the LP disease. © 2016, Indian Council of Medical Research. All rights reserved