A Mutational Hotspot in The LAMP2 Gene: Unravelling Intrafamilial Phenotypic Variation and Global Distribution of The c.877C>T Variant: A Descriptive Study

Objective: Danon disease is defined by a clinical trio of cardiomyopathy, skeletal myopathy, and cognitive impairment.It results from the lysosomal-associated membrane protein-2 (LAMP2) gene variants. The aim of study is determinationof genotype and phenotype of a newly diagnosed Iranian family with a unique phenotype due to a pathogenic variantof the LAMP2 gene along with a phenotypic comparison of all reported patients.Materials and Methods: In this descriptive study, we evaluated the demographic data, clinical features, managementprocedures, as well as genetic analysis of both patients in this newly diagnosed family. Whole genome sequencing(WGS) and in silico structural and functional predictions were applied. A comprehensive search of the c.877C>T variantin LAMP2 was conducted using the PubMed, Google Scholar, VarSome, ClinVar, Human Gene Mutation Database(HGMD), and Franklin databases to identify any genotype-phenotype correlations.Results: Nine patients were carriers of the c.877C>T variant. All patients were male, and displayed variable degreesof left ventricular hypertrophy (LVH) that ranged from mild to severe. All patients exhibited typical cardiac conductionabnormalities consistent with Danon disease. Four underwent heart transplants and survived. Skeletal muscleinvolvement and cognitive impairment were observed in four patients each. The mean age of onset was 14 years. Theproband in this study exhibited an earlier onset of cardiac symptoms.Conclusion: Genetic analysis is the preferred diagnosis approach for Danon disease and can assist families inmanaging affected patients, identify carriers, and assist with future family planning. This study highlights the intrafamilialphenotypic variability of Danon disease. It is possible that variants of this gene may be frequent in Iran

Determinants of perivascular adipose tissue stranding as a novel imaging marker and its relation to inflammatory biomarker high-sensitivity C-reactive protein

Purpose: This study aimed to examine the relationship of perivascular adipose tissue (PVAT) stranding in coronary computed tomography angiography (CCTA) with high-sensitivity C-reactive protein (hsCRP) and the determinants of PVAT stranding in coronary artery disease (CAD) patients. Material and methods: This retrospective cross-sectional study was done by collecting data from CAD patients who were referred to Rajaie Cardiovascular Centre between January 2018 and September 2020, with CCTA and hsCRP test 72 hours apart from the CCTA. PVAT stranding was defined as irregular obscuration of PVAT adjacent to the coronary arteries. An attempt was made to find a correlation between included variables and PVAT stranding by comparing them between 2 groups: patients with and without PVAT stranding. Results: From 92 patients, 31 participants had PVAT stranding, and statistically significant higher levels of hsCRP were detected in them (p = 0.007). We demonstrated significantly higher prevalence of history of hyperlipidaemia (OR = 3.83, p = 0.029), high-risk plaque features (OR = 11.80, p = 0.015), and obstructive coronary luminal stenosis (OR = 3.25, p = 0.025) in patients with PVAT stranding. Also, significantly higher PVAT attenuation was detected in patients with PVAT stranding (p < 0.001) independently from mean attenuation of epicardial fat. Conclusion: PVAT stranding could be used as a novel non-invasive marker in CCTA of CAD patients. More studies focusing on patient outcomes are required to better evaluate the reliability and prognostic value of this marker

Genetic Study of Hypertrophic Cardiomyopathy in Iranian children: The Role of a De novo Variant

Background and Objectives: Hypertrophic cardiomyopathy is a common cardiac disease diagnosed in young adults and rarely detectable in childhood. Hypertrophic cardiomyopathy exhibits considerable diversity in its clinical and genetic characteristics. To date, mutations in multiple genes associated with HCM have been discovered, with the most common ones being MYBPC3 and MYH7 genes. The present study aimed to utilize whole exome sequencing for conducting a genetic analysis of Hypertrophic cardiomyopathy in four children belonging to Iranian families. Materials and Methods: Patients underwent medical evaluation, including clinical assessment, electrocardiography, and echocardiography. Genetic testing was performed after DNA extraction using whole exome sequencing to identify genetic alterations that may be responsible for this disease. In addition, bioinformatic analysis of the genetic changes was carried out using software tools for alignment, variant calling, and interpretation. Finally, the Sanger sequencing method was employed to confirm the genetic variations in the affected individual's family members. Results: The patients were children presenting with initial symptoms, such as syncope and palpitations. They were diagnosed with Hypertrophic cardiomyopathy type 3 and 4 based on the results of electrocardiography and echocardiography. The genetic testing results revealed a pathogenic de novo mutation (c.1208G>A, p.Arg403Gln) in the MYH7 gene. In addition, another disease-causing homozygous nonsense genetic variation (c.3811C>T, p.Arg1271Ter) was identified in the MYBPC3 gene, resulting in the production of a premature protein. Conclusion: This study not only expanded the spectrum of genetic variations associated with Hypertrophic cardiomyopathy disease and aided in genetic counseling for families affected by it but also presented the first variations of the sarcomere gene in Iranian children

Heterozygosity and allele frequencies of the two VNTRs (ApoB and D1S80) in Iranian population

Genetic markers are used for identity testing and paternity analysis depends on knowing the allele frequencies in the population. Minisatellites show allelic variability in the number of repeat units. We have studied the allele frequencies and heterozygosity of two VNTRs (ApoB and D1S80) in Iranian populations. A total of 96 and 82 chromosomes were analyzed by PCR and gel electrophoresis for ApoB and D1S80 respectively. In the ApoB system, allele 37 was the most common followed by allele 35 whereas allele 23 was the most common followed by allele18 at the D1S80 locus. Observed heterozygosity was relatively low in ApoB than D1S80 locus, however, no significant differences were found between observed and expected heterozygosity

A novel stop-gain pathogenic variant in the KCNQ1 gene causing long QT syndrome 1

Abstract Background Inherited primary arrhythmias, such as long QT (LQT) syndromes, are electrical abnormalities of the heart mainly due to variants in 3 genes. We herein describe a novel stop-gain pathogenic variant in the KCNQ1 gene in an Iranian child with LQT syndrome 1. Methods The patient and his family underwent clinical evaluation, electrocardiographic Holter monitoring, and whole-exome sequencing. Sanger sequencing and segregation analysis were used to confirm the variant in the patient and his family, respectively. The pathogenicity of the variant was checked via an in silico analysis. Results The proband suffered from bradycardia and had experienced syncope without stress. The corrected QT interval was 470 ms (the Schwartz score ≥ 3.5), and the Holter monitoring showed sinus rhythm, infrequent premature atrial contractions, and a prolonged QT interval in some leads. Whole-exome and Sanger sequencing showed c.968G > A in 3 affected family members. According to the American College of Medical Genetics and Genomics criteria, c.968G > A was classified as a pathogenic variant. Conclusions The KCNQ1 gene is the main cause of LQT syndromes in our population. The common genes of LQT syndromes should be studied in our country’s different ethnicities to determine the exact role of these genes in these subpopulations

An Iranian Congenital Adrenal Hypoplasia Patient with Elevated Testosterone in Infancy due to a Novel Pathogenic Frameshift Variant in NR0B1

X-linked congenital adrenal hypoplasia due to NR0B1 mutation is characterized by hypogonadotropic hypogonadism (HH) and infertility. Here, we describe a novel pathogenic frameshift variant in NR0B1 associated with congenital adrenal hypoplasia by whole exome sequencing in an Iranian case with high level of testosterone. Clinical evaluations and pedigree drawing were performed. Point mutations, gene conversions, and large deletions of the CYP21A2 gene were checked. WES and segregation analyses were conducted. In silico analysis was also performed for the novel variant. The ACTH, 17-hydroxy progesterone c, and DHEA sulfate values were elevated up to 624.6 pg/mL, 8.6 pmol/L, and 17.8UMOL/L, respectively. No mutation was found in the CYP21A2 gene. WES identified a novel hemizygous frameshift insertion c.218_219insACCA: p.His73GlnfsTer41 variant in the NR0B1 gene with a pathogenic effect according to ACMG criteria. Genetic testing is helpful for differential diagnosis in primary adrenal insufficiency disorders. NR0B1 may be a common cause of congenital adrenal hypoplasia in our population

The Genetic Perspective of Familial Glucocorticoid Deficiency: In Silico Analysis of Two Novel Variants

Familial glucocorticoid deficiency is a rare autosomal recessive genetic disorder which belongs to a group of primary adrenal insufficiency (PAI) and is mainly caused by mutations in the MC2R and MRAP genes. A comprehensive search was conducted to find the reported variants of MC2R and MRAP genes. In silico pathogenic analysis was performed for the reported variants. PCR amplification and sequencing were performed for three patients. Structural analysis, modeling, and interactome analysis were applied to characterize novel MC2R variants and their proteins. About 80% of MC2R-related cases showed the clinical symptoms which were diagnosed at  G (p.Leu43Arg) and c.251T > A (p.Ile84Asn), were found in two patients at the age of above and below 2 years, respectively. Mutations in MC2R and MRAP genes are the main cause of FGD. Genetic studies and in silico analysis will help to confirm the diagnosis

p.Gln318X and p.Val281Leu as the Major Variants of CYP21A2 Gene in Children with Idiopathic Premature Pubarche

Premature pubarche (PP) is the appearance of sexual hair in children before puberty. The PP phenotype may attribute to nonclassic congenital adrenal hyperplasia (NC-CAH). In this study, we investigated the role of CYP21A2 gene variants in patients with PP in the Iranian population. Forty patients (13 males and 27 females), clinically diagnosed with PP, were analyzed for molecular testing of CYP21A2 gene variants. Direct sequencing was performed for the samples. Also, gene dosage analysis was performed for the cases. Fourteen patients (35%) had a mutation of p.Gln318X and p.Val281Leu, out of which 10% had regulatory variants. Approximately 10% of the patients were homozygous (NC-CAH). 78.5% (11/14) of patients had trimodular RCCX of which 5 patients had two copies of CYP21A1P pseudogene. The prevalence of p.Val281Leu was higher than p.Gln318X in PP patients. In conclusion, CYP21A2 variant detection has implications in the genetic diagnosis of PP phenotype. The genetic characterization of the CYP21A2 gene is important for characterizing the variable phenotype of carriers and genetic counseling of PP and NC-CAH patients