Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, ⩽40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.

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Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion, TTN 18 bp I/D and TNNT2 5 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bp deletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR=3.85, P <0.001; and nonLVD versus LVD: OR=1.65, P = 0.035), while TTN 18 bp I/D, TNNT2 5 bp I/D and myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P = 0.037 and LV end systolic dimension, LVESD: P = 0.032). Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population.

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Rheumatic heart disease (RHD) is one of the most severe consequences of rheumatic fever. It has been suggested that angiotensin I-converting enzyme (ACE) may be involved in the increased valvular fibrosis and calcification in the pathogenesis of RHD. We conducted a case-control study to look for association of ACE I/D polymorphism with RHD in Indian population. The study incorporated 300 patients (170 males and 130 females) with RHD, and 200 controls (118 males and 82 females). We also subgrouped RHD patients into mitral valve lesion (MVL) and combined valve lesion (CVL). ACE I/D polymorphism was identified using polymerase chain reaction method. We also performed a meta-analysis of three published studies and the present study (636 RHD cases and 533 controls) to evaluate the association between the ACE I/D polymorphisms and RHD risk. A significant difference in ACE ID and DD genotypes distribution between RHD cases (OR = 1.62, 95% CI = 1.11-2.36 and OR = 2.08, 95% CI = 1.02-4.15, respectively) and corresponding controls was observed. On comparing the ACE genotypes of MVL and CVL subgroups with controls, ID and DD genotypes were also significantly associated with CVL (FDR Pcorr = 0.009, OR = 2.19 and FDR Pcorr = 0.014, OR = 3.29, respectively). Meta-analysis also suggested association of the ACE D allele (FDR Pcorr = 0.036, OR-1.22, 95% CI 1.02-1.45) with RHD. In conclusion, ACE ID and DD genotypes are associated with an increased risk of RHD, particularly CVL. This suggests that the ACE I/D gene polymorphism may play an important role in the pathogenesis of RHD.

Abstract.Background: Left ventricular dysfunction (LVD), followed by fall in cardiac output is one of the major complications in some coronary artery disease (CAD) patients. The decreased cardiac output over time leads to activation of the renin-angiotensinaldosterone system which results in vasoconstriction by influencing salt-water homeostasis. Therefore, the purpose of the present study was to explore the association of single nucleotide polymorphisms (SNPs) in angiotensin I converting enzyme; ACE (rs4340), angiotensin II type1 receptor; AT1 (rs5186) and aldosterone synthase; CYP11B2 (rs1799998) with LVD. Methods and results:The present study was carried out in two cohorts. The primary cohort included 308 consecutive patients with angiographically confirmed CAD and 234 healthy controls. Among CAD, 94 with compromised left ventricle ejection fraction (LVEF 45) were categorized as LVD. The ACE I/D, AT1 A1166C and CYP11B2 T-344C polymorphisms were determined by PCR. Our results showed that ACE I/D was significantly associated with CAD but not with LVD. However, AT1 1166C variant was significantly associated with LVD (LVEF 45) (p value = 0.013; OR = 3.69), but CYP11B2 (rs1799998) was not associated with either CAD or LVD. To validate our results, we performed a replication study in additional 200 cases with similar clinical characteristics and results again confirmed consistent findings (p value = 0.020; OR = 5.20). Conclusion: AT1 A1166C plays important role in conferring susceptibility of LVD.