Amitabh Biswas

Next generation sequencing in cardiomyopathy: towards personalized genomics and medicine

Next generation sequencing (NGS) is perhaps one of the most exciting advances in the field of life sciences and biomedical research in the last decade. With the availability of massive parallel sequencing, human DNA blueprint can be decoded to explore the hidden information with reduced time and cost. This technology has been used to understand the genetic aspects of various diseases including cardiomyopathies. Mutations for different cardiomyopathies have been identified and cataloging mutations on phenotypic basis are underway and are expected to lead to new discoveries that may translate to novel diagnostic, prognostic and therapeutic targets. With ease in handling NGS, cost effectiveness and fast data output, NGS is now considered as a diagnostic tool for cardiomyopathy by providing targeted gene sequencing. In addition to the number of genetic variants that are identified in cardiomyopathies, there is a need of quicker and easy way to screen multiple genes associated with the disease. In this review, an attempt has been made to explain the NGS technology, methods and applications in cardiomyopathies and their perspective in clinical practice and challenges which are to be addressed.

High rate of suicide attempt and associated psychological traits in an isolated tribal population of North-East India

BACKGROUND Cases of suicide documented earlier all over the world reflect the presence of suicide behavior in primitive world at a higher rate compared to general urban population. The cause of such behavior is thought to be different among tribes and mental health was rarely presumed to be associated. In India, several ethnographic narratives described instances of suicides among several tribes, but evaluation of psychological traits were lacking. The present study on Idu Mishmi is an attempt to further validate earlier report of high rate of suicides among them and to evaluate psychological traits. METHODS Interview and administration of Patient Health Questionnaire (PHQ) on 218 individuals comprised the data. Bi-variate analyses and linear multiple regression were done to evaluate psychological traits in suicide behavior. RESULTS In the Idu Mishmi Population suicide attempt (14.22%) was higher than urban population in general (0.4-4.2%) and females were at higher risk. Depression (8.26%) was comparable with earlier reports, whereas anxiety syndrome (6.42%), alcohol abuse (36.24%) and eating disorder like Binge eating (6.42%), Bulimia nervosa (1.38%) were also recorded in the population. LIMITATIONS Absence of psychiatry clinic and mechanism of recording suicide occurrences in remote tribal area is the basic limitation of the study. CONCLUSION Depression and gender turned out to be significant determinants of suicide attempt in the studied population, whereas alcohol abuse was not a significant factor.

Clinical characterization of Idiopathic Restrictive Cardiomyopathy having rare variant (E949K) in β-cardiac myosin heavy chain gene

Background Idiopathic Restrictive cardiomyopathy (IRCM) and hypertrophic cardiomyopathy (HCM) reflects the same or very similar disorders showing restrictive physiology with different names due to discretionary crosscuts in the LV wall thickness rather than two separate distinct diseases. The perspective of this study is to clinically evaluate the IRCM proband and comparison between the two distinct disease phenotype IRCM and HCM as an outcome of same genotype i.e.E949K in gene MYH7.

Epidemiology of cardiomyopathy - A clinical and genetic study of hypertrophic cardiomyopathy: The EPOCH-H study

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder with the prevalence of 1 in 500 globally. HCM is clinically characterized by thickening of the wall of the heart, predominantly left ventricle (LV), and interventricular septum (IVS). Our study aims to report the demographical, clinical and genetic profile of Indian HCM patients. Methods: HCM patients were recruited on the basis of WHO criteria. The clinical phenotypes were analyzed using electrocardiography, two-dimensional electrocardiography, and hotspot region of the MYH7 gene was sequenced for all patients as well as for controls. Results: There were 59 patients with a clinical diagnosis of HCM with a preponderance of disease in males with a ratio (men, women) of 5.5:1. Average age of onset of the disease was late 30 s (39.2 ± 14.5) with familial HCM accounting for 18% (n = 9) for total HCM families (n = 50). Nonobstructive kind of HCM was more prevalent as compared to obstructive HCM (66.1% vs. 33.9%). Average posterior wall LV thickness of the HCM patients was 16 ± 4.8 mm and IVS thickness was 21 ± 8.3 mm with familial patients having greater wall thickness as compared to sporadic patients. Sequencing of hotspot region of MYH7 identified three mutations in three different patients. Two mutations were found to be segregating in familial cases. Conclusion: HCM is more prevalent in males with a predominance of hypertrophic nonobstructive cardiomyopathy form. Eighteen percent of cases were familial and showed an early onset of the disease and worse prognosis as compared to sporadic cases. Hotspot sequencing of MYH7 only explains 6% of its genetic basis. More of the candidate genes need to be screened through advanced techniques like next generation sequencing to identify the causal genes which could make us understand the mechanistic pathways.

Epidemiology of cardiomyopathy - A clinical and genetic study of dilated cardiomyopathy: The EPOCH-D study

Background: Dilated Cardiomyopathy (DCM) is a genetic disorder where a heterogeneous group of cardiac-muscles are involved and is characterized by ventricular dilatation, impaired systolic function, reduced myocardial contractility with left ventricular ejection fraction (LVEF) less than 40%. Our study aims to report the Demographic, Clinical and Genetic profile of Indian Dilated Cardiomyopathy patients. Methodology: All patients were recruited with prior written informed consent and are of Indian origin. Results: In a total of 80 DCM patients, the prevalence was higher among males. In males, mean age of onset was comparatively less than females. In this cohort, 40% had familial inheritance. Sixty two percent of DCM patients belong to NYHA functional class II with ejection fraction (EF) ranging between 21-30% and, around one third of the patients had atrial fibrillation (AF). Genetic screening revealed a novel splice site mutation LMNA (c.639+ G>C) and a rare variant MYH7 (c.2769 C>T) in a patient and insilico analysis of both variants suggested functional changes that were considered pathogenic. We report 3% and 4% occurance of variants, each in LMNA and MYH7, where as reported frequencies of these genes are 6% LMNA and 4% MYH7. Conclusions: DCM is often familial and all possible candidate genes should be screened to identify mutations. Such type of exercise may help in the identification of mechanistic pathways. Next generation sequencing platforms may play an important role in this respect in future.

A novel donor site mutation in LMNA gene leading to severe form of Dilated Cardiomyopathy in a proband of a family from Bihar, India

Methods The proband underwent Echocardiography and ECG to confirm the diagnosis. 5ml blood was collected and DNA was extracted using Phenol-chloroform method. The hot spot regions exon 23 of MYH7 gene, exon3 and exon 4 along with the intron3 of LMNA gene were sequenced using Sanger sequencing (ABI 3730xl). ACE 287bpI/D and TNNT25bpI/D polymorphisms were also genotyped. In silico analysis of this novel mutation by using softwares, Human splicing finder (HSF) and MaxENT to understand the effect of mutation on splicing. The study was ethically approved by Institutional committee and informed written consent was taken from all participants.