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Background: Heart failure is a hallmark of severe hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Several mutations in the β-MYH7 gene lead to hypertrophic cardiomyopathy. Recently, causative mutations in the β-MYH7 gene have also been detected in DCM from different populations. Methods: Here, we sequenced the β-MYH7 gene in 137 Indian DCM patients and 167 ethnically matched healthy controls to detect the frequency of mutations and their association. Results: Our study revealed 27 variations, of which 7 mutations (8.0%) were detected exclusively in Indian DCM patients for the first time. These included 4 missense mutations—Arg723His, Phe510Leu, His358Leu, and Ser384Tyr (2.9%); a frameshift mutation—Asn676_T-del (1.5%); and 2 splice-site mutations (IVS17+2T) T>G and (IVS19-1G) G>A (3.6%). Remarkably, all 4 missense mutations altered evolutionarily conserved amino acids. All 4 missense mutations were predicted to be pathogenic by 2 bioinformatics tools—polymorphism phenotyping v2 (PolyPhen-2) and sorting intolerant from tolerant (SIFT). In addition, the 4 homology models of β-MYH7—p.Leu358, p.Tyr384, p.Leu510, and p.His723—displayed root-mean-square deviations of ∼2.55 Å, ∼1.24 Å, ∼3.36 Å, and ∼3.86 Å, respectively. Conclusions: In the present study, we detected numerous novel, unique, and rare mutations in the β-MYH7 gene exclusively in Indian DCM patients (8.0%). Here, we demonstrated how each mutant (missense) uniquely disrupts a critical network of non-bonding interactions at the mutation site (molecular level) and may contribute to development of dilated cardiomyopathy (DCM). Therefore, our findings may provide insight into the understanding of the molecular bases of disease and into diagnosis along with promoting novel therapeutic strategies (through personalized medicine). Résumé: Introduction: L’insuffisance cardiaque est une caractéristique de la cardiomyopathie hypertrophique grave et de la cardiomyopathie dilatée (CMD). Plusieurs mutations dans le gène β-MYH7 conduisent à la cardiomyopathie hypertrophique. Récemment, les mutations causales dans le gène β-MYH7 ont également été détectées au sein de différentes populations atteintes de CMD. Méthodes: Ici, nous avons séquencé le gène β-MYH7 de 137 patients indiens atteints de CMD et de 167 témoins sains appariés selon l’origine ethnique pour détecter la fréquence des mutations et leur association. Résultats: L’étude nous a permis de révéler 27 variations, dont sept mutations (8,0 %) étaient exclusivement détectées chez les patients indiens atteints de CMD pour la première fois. Parmi ces mutations, nous avons observé quatre mutations faux-sens—Arg723His, Phe510Leu, His358Leu et Ser384Tyr (2,9 %), une mutation par déphasage—Asn676_T-del (1,5 %) et deux mutations des sites d’épissage (IVS17+2T) T>G et (IVS19-1G) G>A (3,6 %). Étonnamment, les quatre mutations faux-sens changeaient les acides aminés évolutivement conservés. Selon deux outils bioinformatiques—PolyPhen-2 (de l’anglais, polymorphism phenotyping v2) et SIFT (de l’anglais, sorting intolerant from tolerant), les quatre mutations faux-sens devaient être pathogènes. De plus, les quatre modélisations de β-MYH7 par homologie—p.Leu358, p.Tyr384, p.Leu510 et p.His723—affichaient de façon respective des écarts quadratiques moyens de ∼2,55 Å, ∼1,24 Å, ∼3,36 Å et ∼3,86 Å. Conclusions: Dans la présente étude, nous avons détecté de nombreuses nouvelles mutations, uniques et rares, dans le gène β-MYH7, exclusivement chez les patients indiens atteints de CMD (8,0 %). Ici, nous avons démontré comment chaque mutant (faux-sens) perturbe de manière unique un réseau essentiel d’interactions non liantes au site de mutation (moléculaire) et peut contribuer à la survenue de la CMD. Par conséquent, les conclusions de notre étude peuvent donner un aperçu des bases moléculaires de la maladie et du diagnostic tout en favorisant la promotion de nouvelles stratégies thérapeutiques (par la médecine personnalisée).

Background Type 1 diabetes mellitus (TIDM) is a polygenic disorder with the involvement of several genetic and environmental risk factors. Mutation in genes namely ABCC8 and KCNJ11 disrupt the potentiality of KATP channel and regulates the secretion of insulin by detecting a change in the blood glucose level and consequently maintains glucose homeostasis. The present study was designed to investigate the association of ABCC8 and KCNJ11gene polymorphisms with type 1 diabetes. A case-control study was conducted enrolling 60 cases suffering from T1DM and 60 healthy controls of comparable age and sex. Gene variations were determined by PCR-RFLP and ARMS-PCR method. Results The ABCC8-3C > T (rs1799854) variation was found to be significantly associated with T1DM (pT (rs1801261) polymorphism of ABCC8 with T1DM. A significant association was observed for genetic variation at rs5219 C>T polymorphism and the frequency of TT genotype was found to be significantly higher in patients (46.7%) than in controls (21.7%), indicating the significant role of the KCNJ11 rs5219 variant in T1DM susceptibility (pA (rs5215) polymorphism of KCNJ11 with T1DM. In addition, haplotype analysis of the two genes revealed four haplotypes such as T-C-G-T, T-C-A-T, C-C-G-T, and T-T-G-T as risk haplotypes for type 1 diabetes (p Conclusions The present study highlights the importance of personalized medicine based on individual genetic profile.

Background: Peroxisomal acyl CoA oxidase deficiency is a very rare neurodegenerative disorder characterised by postnatal hypotonia, seizures, and neurological regression in early infancy. Case Presentation: Here, we present a case of two children in a family affected with peroxisomal acyl CoA oxidase deficiency. Early onset of hypotonia, seizures, and psychomotor delay was observed in both the sibs. Plasma levels of very long chain fatty acids showed normal levels of phytanic acid, pristanic acid, C22, C24, C26, C26/C22, and C24/C22 ratios. Here, we describe a case where women in her second trimester and with two affected siblings with peroxisomal acyl CoA oxidase deficiency was referred to institute for genetic counselling. Conclusion: Clinical exome analysis of the couple, two affected sibs and the fetus adds new insight into the clinical, neuroradiological, and molecular aspects of this disorder that represents one of the rarer inherited defects of peroxisomal function.

Background: Pseudo-TORCH syndrome (PTS) is a group of autosomal recessive disorders that clinically and radiologically mimic TORCH congenital infections. The prevalence of pseudo-TORCH syndrome 2 is 1 in 1,000,000 cases worldwide. This novel disorder is extremely rare, and is generally detected by prenatal diagnosis through next generation sequencing (NGS) during pregnancy. In this study, a familial case of pseudo-TORCH syndrome 2 with novel non-sense mutation in the ubiquitin-specific peptidase 18 (USP 18) gene in the parents was reported, who are heterozygous asymptomatic carriers; however, all children have inherited a homozygous pathogenic form of USP18, which is an important negative regulator of type I interferon (IFN) signal transduction. To the best of our knowledge, this is the first case of a novel mutation of USP18 seen in a family with pseudo-TORCH syndrome 2 (PTS 2) from India. Case Presentation: A 23-year-old pregnant woman with bad obstetric history, including intrauterine and neonatal mortality was referred to the Institute of Genetics in the year 2021 for clinical and genetic evaluation. Advanced clinical exome sequencing of the parents and the fetus revealed heterozygous carrier status in parents and homozygous mutation in USP 18 gene in the progeny leading to pseudo-TORCH-2 syndrome. Conclusion: The present case highlights the significance of carrier screening, prenatal diagnosis, and genetic counseling in couples with bad obstetric history for the detection of rare genetic disorders with poor prognosis.

Recurrent pregnancy loss is an important reproductive issue with a heterogeneous etiology where two or more consecutive abortions occur before 20 weeks of gestation. Approximately 15% of all clinically recognized pregnancies result in miscarriage with an incidence of 1 in 300 cases. Couples, who experience repeated pregnancy loss before three months of gestation, mostly have fetuses with chromosomal aneuploids. A non-consanguineous couple with a married life of 4 years was referred to the Institute with a clinical history of three first trimester abortions. Karyotype analysis revealed a balanced autosomal translocation between chromosomes 4 and 6 with 46, XX, t (4;6)(q35; q22) karyotype in the female and normal 46, XY in the male partner. Therefore, the siblings and the couple were suggested for extended genetic counseling. Interestingly, similar translocation was seen in her father and three sisters, whereas her mother and elder sister showed a normal chromosomal constitution, indicating the paternal inheritance.

Background Mutations in β-MYH7 gene is a main genetic cause of cardiomyopathy and sudden cardiac arrest, yet the molecular mechanisms have not been fully understood. Objectives To identify variations in β-MYH7 gene and their possible mechanistic role in cardiomyopathies among Indian women. Methods We sequenced all exons and their flanking regions of the β-MYH7 gene in 188 Indian women consisting of 33 hypertrophic cardiomyopathy (HCM), 48 dilated cardiomyopathy (DCM), and 107 healthy controls. Results Our study showed 21 variations in β-MYH7 gene, including 7 novel mutations. In addition, we compared this dataset with our previously studied datasets of seven other sarcomere genes (ACTC, TNNT2, MYL2, MYBPC3, TPM1, TNNI3, and MYL3) and found no causative mutation, confirming the nonexistence of compound heterozygosity. Interestingly, we detected a Val431Met mutation exclusively in patients, and its pathogenicity has been predicted using the protein homology model. In native, Val431 is evolutionarily conserved across many species. In the homology model, mutant Met431 gets further buried in the hydrophobic core by creating an aberrant hydrophobic interaction with Leu352. As a result, it probably reduces the spatial distances between other hydrophobic interactions in the hydrophobic core that may produce steric hindrance and strain. It may lead to deviation in the structure (root means square deviation [RMSD] of ~3.9), and might possibly causing the cardiac remodeling and cardiomyopathy. Conclusion We identified a novel Val431Met mutation, exclusively in patients, and its homology model p.Met431 has profoundly increased the mechanistic understanding of disease specifically in personalized medicine, to block/inverse/diminish the disease phenotype.

Background: Uterine leiomyomas are steroid hormone dependent myometrial neoplasms of female genital tract which appear after menarche and regress at menopause. The present study evaluated the role of ER-β gene polymorphisms (rs3020449 C/T, rs3020450 G/A, rs1271572 G/T, rs1256049 G/Aand rs4986938 G/A) in the etiology of disease. Methods: A total of 150 clinically, ultrasonographically evaluated uterine leiomyoma patients and an equal number of individuals as controls were considered for the present study. Genotype analysis was carried out by TETRA Primer Amplification Refractory Mutation System–PCR for promoter polymorphisms and PCR- RFLP method was done for exonic polymorphisms followed by agarose gel electrophoresis. The strength of the association of ER-β gene polymorphisms between controls and patients were measured by appropriate statistical methods. Results: An increased frequency of T/T genotype and T allele of rs3020449, AA genotype and A allele of rs3020450, T/T genotype and T allele of rs1271572, AA genotype and A allele of rs1256049 and A/A genotype and A allele of rs4986938 was observed in cases when compared with controls. Conclusion: The study indicates that the ER-β gene polymorphisms may act as a major genetic regulator in the etiology of uterine leiomyomas.

Cardiac hypertrophy is an adaptive response to stress, in order to maintain proper cardiac function. However, sustained stress leads to pathological hypertrophy accompanied by maladaptive responses and ultimately heart failure. At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in myocyte size, reactivation of the fetal gene markers, disassembly of the sarcomere and transcriptional remodelling which are regulated by heart-specific transcription factors like MEF2, GATA4 and immediate early genes like c-jun and c-fos.2. It has been explored and established that the hypertrophic process is associated by oxidative stress and mediated by pathways involving several terminal stress kinases like P38, JNK and ERK1/2. Stilbenoids are bioactive polyphenols and earlier studies have shown that imine stilbene exert cardioprotective and anti aging effects by acting as modulators of Sirt1. The present study was aimed at designing and synthesizing a series of imine stilbene analogs and investigate its anti hypertrophic effects and regulatory mechanism in cardiac hypertrophy and apoptosis. Interestingly one of the analog, compound 3e (10 μM) alleviated isoproterenol (ISO, 25 μM) induced hypertrophy in rat cardiomyocyte (H9c2) cells by showing a marked decrease in the myocyte size. Further, compound 3e also restored the cardiac function by activating the metabolic stress sensor, AMPK. Moreover, molecular docking studies showed stable binding between compound 3e and GSK3β suggesting that compound 3e may directly regulate GSK3β activity and ameliorate ISO-induced cardiac hypertrophy. In agreement with this, compound 3e also modulated the crosstalk of all the hypertrophy inducing terminal Kinases by bringing down the expression to near control conditions. The compound also relieved H2O2 (100 μM) mediated ROS and normalized abnormal mitochondrial oxygen demand in hypertrophic conditions indicating the possibility of the compound to show promise in playing a role in cardiac hypertrophy.

Recurrent pregnancy loss (RPL) is defined as two or more pregnancies losses occurring before 20 weeks of gestation and affecting 1-3% of the couples. Chromosomal abnormalities, uterine defects, thrombophilia, immunological factors, endocrine and metabolic factors are the known risk factors involved in the causation of recurrent pregnancy loss in 50% of the cases. However, remaining 50% of the recurrent pregnancy loss cases are unexplained. A lot of research is going on in the area of recurrent pregnancy loss globally and the results are inconsistent due to study designs, sample size, ethnicity etc. The present review took an insight into the overall risk factors involved in the causation of explained recurrent pregnancy loss to help the researchers to identify the origin of pregnancy loss and to provide best investigation and treatment strategy for women with recurrent pregnancy loss.

The case report presents 5 years old male proband with Joubert syndrome (JS) referred to the Institute with the complaint of developmental delay. Mutation analysis in the proband by MLPA showed homozygous duplication in exon 7 of SMN2 gene. Further, next generation sequencing (NGS) based gene panel study showed one copy of c.746G>A (p.R249H) variant of uncertain significance in exon 5 of TRPV4 gene in heterozygous condition. The same variant was identified in the probands father. Prenatal diagnosis in proband’s mother who was pregnant, revealed heterozygous missense variants of uncertain significance at c.578C>G (p. Thr193Arg) in exon 4 of PNPLA8 gene and c.862C>T (p. Arg288Cys) in exon 6 of KCNH1 gene in the developing foetus. Thus, the advanced genetic analysis along with clinical findings and typical imaging will help in appropriate diagnosis and management of the Joubert syndrome.

Introduction Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is a genetic disorder characterized by fibrofatty replacement of right ventricle. Extensive research revealed the involvement of desmosomal, non-desmosomal and modifier genes in the etiology of the ARVC/D. Further, environmental factors with modifier genes influence the severity of the disease. One of the well-known modifier genes is HSP90α polymorphism, which is involved in protein folding and regulation as well as apoptosis etc. Therefore, in this study, an investigation was carried out to find the possible association between HSP90α polymorphism and ARVC/D. Material and methods This study included 240 healthy control samples without any family history of cardiac diseases and 61 ARVC/D patients. Diagnosis of patients was carried out using ECG and 2-D echocardiography, following revised diagnostic criteria: definite, borderline diagnosis and possible diagnosis. Scoring of genotypes was carried out by allelic-specific PCR. Results A statistically significant association was observed between HSP90α polymorphism and ARVC/D. In codominant and overdominant models, ‘C/G’ was found to be risk conferring. Further, in dominant model, ‘C/G’ and ‘G/G’ genotypes were susceptible for ARVC/D. Moreover, ‘G’ allele which was predominant in ARVC/D was found to risk conferring towards ARVC/D. Conclusion These findings suggest that possible role ofHSP90α polymorphism in the etiology of ARVC/D. The ‘G’ allele of HSP90α polymorphism damages the 3-D native conformations, which is required for the interaction between client proteins such as desmosomes, ryanodine receptor-2 and sodium channel leading to mislocalization of these proteins. Furthermore, loss of inhibitory interaction between HSP90α protein and Apaf-1 trigger apoptosis.

Long QT syndrome (LQTS) is a rare primary cardiac electrophysiological disorder with characteristic symptoms of syncope, tachyarrhythmia and torsades-de-pointes. It is the outcome of mutations in genes encoding ion channels that function as voltage regulators. Heat shock protein (HSP) 90 is a molecular chaperone that plays vital roles in a variety of cellular processes, one of which is folding of nascent polypeptide chains into their native forms. The main objective of this study was to screen for HSP90 Q488H (C > G) polymorphism in patients with LQTS and identify its risk towards LQTS manifestation.

Objective To explore the combined association of MTHFR gene polymorphisms (C677T, A1298C) with spontaneous abortions in a triad group from Telangana State of South Indian population. Materials A total of 80 case families with spontaneous abortions and 100 control families with medically terminated pregnancies were considered. Fetal tissue with Methods DNA was isolated by phenol-chloroform method from both tissue and peripheral blood samples and then genotyped using Amplification Refractory Mutation System–Polymerase Chain Reaction followed by agarose gel electrophoresis. Genotype and allelic frequencies of MTHFR polymorphisms were determined by Odds Ratio with 95% Confidence Intervals and level of significance was considered at p value Results Statistically significant association was observed with 677C/T polymorphism in case fetal (p = 0.006), maternal (p Conclusion The present study supports the major role of MTHFR gene polymorphisms in the etiology of spontaneous abortions.

Myocyte enhancer factor-2A (MEF2A), encoding a member of the MEF2 family of transcription factors, has been identified for primary CAD and MI without other accompanying clinical feature. It plays a role in vascular ontogeny and shows its predominant expression in the coronary artery endothelium. In the present study, we sought to evaluate the possible role of Mef2A polymorphisms as a risk determinant of CAD.A total of 300 angiographically documented cases and 300 healthy controls were recruited for the study. Polymorphisms of Mef2A 279 C > T in exon 8 and 452 G > T, 481 A > G in exon 11 were determined by PCR-RFLP method. The Mef2a 279 C > T variation and 452 G > T was found to be significantly associated with CAD (p G polymorphism with CAD in addition haplotype analysis revealed that T-G-A and C-T-A haplotype was found to be about three & single fold higher in CAD than controls with the association being statistically significant (p

Background Ovarian cancer is the most common cancer among women worldwide. Estrogen plays an important role in follicle formation and maturation of oocyte via its receptor (ER). It has a special interest as their protein levels are always elevated in premalignant and malignant cancer cells and are over expressed in different tumors with a favourable prognosis. The present study is aimed to evaluate the role of ER-α gene ( rs2234693) PVUII polymorphism in the etiology of ovarian cancer. Materials and methods A total of eighty clinically and histopathologically confirmed ovarian cancer patients and 100 healthy control subjects were included in the present study. Demographic details along with blood samples were collected from all the subjects. DNA was extracted, amplified and genotyped for ER-α gene PVUII polymorphism by PCR-RFLP method followed by agarose gel electrophoresis. Statistical methods were applied to test for the significance of the results. Results The genotype frequencies revealed 50% of wild homozygotes (PP), 33.75% of heterozygotes (Pp), 16.25% of mutant homozygotes (pp) in the diseased group and 79% of wild homozygotes (PP), 12% of heterozygotes (Pp), 9% of mutant homozygotes (pp) in the control group. There is a significant increase of p allele in patients compared to controls. Conclusion The present study thus indicates the possible association of PVUII polymorphism of ER-α gene in the etiology of ovarian cancer.

Hypertrophic cardiomyopathy is a multifactorial disorder, with mutations implicated in 12 sarcomeric and cytoskeletal genes accounting for genotypic and phenotypic heterogeneity, making genetic and clinical diagnosis much more challenging. The genetics of HCM has been studied for more than two decades in various ethnic and racial groups reporting many novel pathogenic variations. It is interesting to know that the Indian population owing to its varied genetic pool and vast ethnic background is still a potential ground for novel genetic variations. Hence, the present study considered screening of MYBPC3 gene, which is highly implicated in HCM. Molecular screening was carried out by PCR based SSCP analysis in 100 controls and 100 HCM patients. The variations were further confirmed by sequencing. In silico analysis was carried out to analyze the effect of the respective variations. The study revealed seven variations viz.: one missense variation in exon 5 (p.Val158Met), two synonymous variations in exon 17 (p.Ala432 =; p.Asp431 =), two intronic variations in exon 14 (c.1223 + 2T > G, c.1091 − 24C > T), one intronic variation in exon 21 (c.1927 + 89C > G) and one synonymous variation in exon 26 (p.Val849Val). The synonymous and intronic variations though are non-pathogenic, may still have a regulatory role in the splicing mechanism, resulting in stoichiometry changes mandatory in protein-protein interactions. Their effect may be further influenced by the modifier genes and environmental factors accounting for severe clinical manifestations and phenotypic heterogeneity. Hence, the present study describes the significance of intronic and synonymous variations of MYBPC3 gene in the phenotype.

Coronary artery disease (CAD) remains to be the prominent health problem in India, and its incidence is growing in developing countries as well. Matrix metalloproteinase 1 (MMP 1) is highly expressed in disruption-prone shoulder regions of the fibrous plaques. The present study aims to investigate association of MMP 1 gene polymorphisms (− 1607 1G/2G) and serum circulating levels with CAD. The study includes 300 CAD patients, 100 FDRS, and 300 controls. ELISA and PCR-RFLP were performed to determine MMP 1 serum levels and genotypes respectively. MMP1 levels were high in CAD patients, followed by FDRS compared to controls (2.15 ± 1.2 ng/ml; 1.46 ± 1.04 ng/ml and 0.96 ± 0.53 ng/ml) respectively. ROC analysis showed the AUC at 95% CI of serum MMP-1 to be 0.83 and 0.73–0.94, respectively. The optimal cut-off point (sensitivity; specificity) of serum MMP 1 was > 1.5 ng/ml (0.74; 0.90). The 2G/2G genotype was associated with high MMP 1 circulating levels in CAD patients, and a similar trend was observed in FDRS and controls. The pre-mRNA secondary structure of the 2G allele is much more stable than 1G allele. Our results suggest MMP 1 serum levels and polymorphism as potential independent prognostic markers for future cardiovascular events. These may also help to stratify CAD patients and to identify susceptibility for CAD in asymptomatic healthy FDRS.

Background Uterine Leiomyomas (UL) are non-cancerous single celled mass of uterine smooth muscles distinguished by presence of large amounts of collagen, fibronectin and proteoglycans. Tumor necrosis factor-α (TNF-α), an inflammation inducing cytokine, plays a major role in various disorders of the immune system; is involved in tumor development and progression. It is proposed to study the influence of three functional promoter polymorphisms of TNF-α viz -238G/A, -308G/A and -1031T/C in the development and progression of UL. Methodology Study included 146 individuals positive for uterine fibroids and 150 healthy individuals. Genomic DNA was isolated from white blood corpuscles and subjected to PCR-RFLP analysis and Allele Specific PCR (ARMS). The significance of the obtained data in controls and patients was estimated and computed by adopting appropriate statistical tools. Results In this study an association between TNF-α -1031T/C polymorphism and UL was reported. A significant association of the TC genotype (χ(2) - 14.34; p=0.0008) and the C allele (χ(2) - 5.898 p=0.015) with uterine leiomyomas was observed. Likewise odds risk estimates of 2.56 (95% CI 1.56-4.20, p=0.0007) revealed a significant association of TC genotype and C allele with uterine leiomyomas. Conclusions "TC" genotype and "C" allele of rs1799964 (-1031T/C) is associated with higher risks to leiomyomas. The "C" allele of -1031T/C results in an increased expression TNF-α leading to smooth cell proliferation and tumor progression, hence, may be a relevant molecular marker in the identification and establishment of UL.

PURPOSE: The study estimates the association of VEGF gene polymorphism (-1154 G/A, -2549 I/D, -2578 C/A, and +936 C/T) in recurrent pregnancy loss from South Indian population. METHODS: A total of 100 couples with the history of recurrent pregnancy loss and 100 couples with medically terminated pregnancies were considered. Fetal tissues with

Background: Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes – 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities. Objectives: Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them. Method: For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India. Results: Our study revealed a total of 10 variations – 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls. Conclusions: MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians.

Background: Alzheimer Disease (AD), the most common form of dementia, is a progressive and irreversible neurodegenerative disorder. Promising preventative strategies includes identification of potential modifiable risk factors for AD that could help identify individual who are at risk of AD. This study focuses on identifying biochemical factors associated with non- familial AD. Methods: One hundred and ten individuals which included 55 AD patients and 55 healthy controls were recruited for the study. Patients clinically diagnosed by a neurologist as AD and controls with no clinical or family history of any neurological disease were subjected to Mini-Mental State Examination (MMSE) were evaluated for fourteen relevant biochemical markers using commercial kits. MDR analysis was carried out which is considered a basic machine learning tool for understanding the role of interaction and combination of the factors towards the outcome. PCA is performed to support the MDR interpretation. Through clustering analysis the probably causative factors towards the disease can be identified. Results: MDR analysis revealed that the overall best fit model included 10 factors which had a maximal testing accuracy of 61%, cross-validation consistency of 8/10. PCA analysis has further reduced the factors to Iron, TSAT, HDL, VitB12, FA, and Hcy which are important in disease initiation/progression. Apart from the cases, 9% of the controls who had lower MMSE also had low Iron, TSAT, HDL, VitB12, FA, and high Hcy. Conclusion: As per the results obtained, we would suggest a medical practice where, screening individuals above the age of 55 years with both MMSE and selected biochemical parameters (Iron, TSAT, HDL, VitB12, FA, and Hcy) should be carried out to identify those at risk of developing AD. Higher risk individuals can be suggested for modifications in diet/life style, enhancing certain nutritional components which may constitute promising strategies in postponing, slowing, and/or preventing cognitive decline in AD.

Long QT syndrome (LQTS) is a rare cardiac disorder caused due to mutations in genes encoding ion channels responsible for generation of electrical impulses. The heat shock protein (HSP)-70 gene, expressed under conditions of stress, plays a cardioprotective role when overexpressed and helps in the proper folding of the nascent proteins synthesized by the cellular machinery. We aimed to identify the role played by HSP-70 gene polymorphisms in the pathogenesis of LQTS. Study included 49 LQTS patients, 71 family members, and 219 healthy individuals recruited from an ethnically matched population. Genotyping of the single-nucleotide polymorphisms (SNPs) rs1043618 (HSP-70-1, +190G/C), rs1061581 (HSP-70-2, +1267A/G), and rs2227956 (HSP-70-hom, +2437T/C) was performed by PCR-RFLP analysis, and the results were analyzed statistically at 95 % confidence interval and p ≤ 0. 05. The “C” allele of HSP-70-1 (+190G/C) and “G” allele of HSP-70-2 (+1267A/G) showed strong association with LQTS phenotype. The haplotype group C-G-T consisting of two risk alleles was significantly associated with the disease condition. Multifactor dimensionality reduction analysis further substantiated that the three-allele model influences the outcome of the phenotype highlighting the effect of modifiers in the etiology of LQTS. As HSP-70 influences the channel assembly and maturation/trafficking of the ion channel proteins, the alleles C of the HSP-70-1 and G of the HSP-70-2 loci and the haplotype group C-G-T could be considered a diagnostic biomarker in the identification of the LQTS phenotype with a potential to affect the progression and modification of the disease phenotype.

The SCN5A gene encodes for the INa channel implicated in long QT syndrome type-3 (LQTS-type-3). Clinical symptoms of this type are lethal as most patients had a sudden death during sleep. Screening of SCN5A in South Indian cohort by PCR-SSCP analyses revealed five polymorphisms — A29A (exon-2), H558R (exon-12), E1061E and S1074R (exon-17) and IVS25 + 65G > A (exon-25) respectively. In-silico and statistical analyses were performed on all the polymorphisms. Exon-2 of SCN5A gene revealed A282G polymorphism (rs6599230), resulting in alanine for alanine (A29A) silent substitution in the N-terminus of SCN5A protein. Exon-12 showed A1868G polymorphism (H558R — rs1805124) and its ‘AA’ genotype and ‘A’ allele frequency were found to be higher in LQTS patients pointing towards its role in LQTS etiology. Two polymorphisms A3378G (E1061E) and the novel C3417A (S1074R) were identified as compound heterozygotes/genetic compounds in exon-17 of SCN5A located in the DIIS6–DIIIS1 domain of the SCN5A transmembrane protein. IVS25 + 65G > A was identified in intron-25 of SCN5A. The ‘G’ allele was identified as the risk allele. Variations were identified in in-silico analyses which revealed that these genetic compounds may lead to downstream signaling variations causing aberrations in sodium channel functions leading to prolonged QTc. The compound heterozygotes of SCN5A gene polymorphisms revealed a significant association which may be deleterious/lethal leading to an aberrant sodium ion channel causing prolonged QTc., Highlights • Screening of SCN5A in South Indian cohort showed 4 reported and 1 novel polymorphism. • Compound heterozygotes found to have a significant association with LQTS • Genetic compounds maybe deleterious leading to an aberrant sodium ion channel

The present study is a triad study designed to determine the co-relation of IL-10 -819C/T promoter polymorphism with the risk of spontaneous abortions.A total of 50 families with spontaneous abortions and 60 families with medically terminated pregnancies were considered for the present study. Fetal tissue of less than 20 weeks of gestation along with peripheral blood from all the couples was collected in this study.A standard amplification refractory mutation system-polymerase chain reaction was carried out to determine the IL 10 genotype in all the subjects. Odd's ratio and their respective 95% confidence intervals were used to determine the strength of association between IL-10 promoter gene polymorphism and spontaneous abortions.The study revealed a statistically significant association of IL-10 -819C/T polymorphism between the two family groups among fetuses (p=0.0000003) and mothers (p=0.0000001). No significant difference was observed in the genotype distribution of IL-10 among fathers.An increased frequency of TT genotype and T allele was observed in spontaneously aborted fetuses and their mothers compared to respective controls. In conclusion, IL-10 C -819T gene promoter polymorphism may act as a major genetic regulator in the etiology of spontaneous abortions.

Spontaneous abortion or miscarriage is the natural death of an embryo or foetus in the early stages of prenatal development. Interleukin-10 is an anti-inflammatory cytokine, produced by human cytotrophoblasts, and defects in its production result in specific pathological conditions during pregnancy. The present study is aimed to evaluate the association of IL-10 -1082G/A polymorphism in spontaneous abortions by comparing foetal, maternal and paternal groups—a triad study. A total of 50 families with spontaneous abortions and 60 families with medically terminated pregnancies were considered for the present study. DNA from foetal tissue and parental blood samples were extracted, and the genotype analysis of IL-10 -1082G/A promoter polymorphism was carried out by amplification refractory mutation system-polymerase chain reaction followed by agarose gel electrophoresis. A statistical analysis was applied to test for the significance of the results. There was a statistically significant difference in the distribution of AA genotypes and A allele of IL-10 -1082G/A between the two family groups among foetuses (P = 0.0002) and mothers (P = 0.00005). The paternal group showed no significant difference in the genotype distribution of IL-10 between cases and controls. In conclusion, IL-10 G-1082A gene promoter polymorphism may act as a major genetic regulator in the etiology of spontaneous abortions.

To investigate the relationship between IL-6 -174G/C promoter polymorphism and preeclampsia.A total of 140 preeclamptic women and 135 women with normal pregnancy were considered for the present study. A standard amplification refractory mutation system PCR was carried out for genotyping of IL-6 G-174C promoter polymorphism. Genotypic distribution was compared with values predicted by Hardy-Weinberg equilibrium using χ (2) test. Odds ratios and their respective 95 % confidence intervals were used to measure the strength of association.The frequencies observed, CC, GC and GG, were 53.5, 26.6 and 20 % in patients and 26.6, 23.7 and 49.6 % in the controls. There is a significant difference in the distribution of genotypes and alleles of IL-6 G-174 C between the two groups.The present study suggests that the IL-6 -174 promoter polymorphism is a major genetic regulator in the etiology of early-onset preeclampsia.