In Silico Characterization of Pathogenic Homeodomain Missense Mutations in the PITX2 Gene.

Paired homologous domain transcription factor 2 (PITX2) is critically involved in ocular and cardiac development. Mutations in PITX2 are consistently reported in association with Axenfeld-Rieger syndrome, an autosomal dominant genetic disorder and atrial fibrillation, a common cardiac arrhythmia. In this study, we have mined missense mutations in PITX2 gene from NCBI-dbSNP and Ensembl databases, evaluated the pathogenicity of the missense variants in the homeodomain and C-terminal region using five in silico prediction tools SIFT, PolyPhen2, GERP, Mutation Assessor and CADD. Fifteen homeodomain mutations G42V, G42R, R45W, S49Y, R53W, E53D, E55V, R62H, P65S, R69H, G75R, R84G, R86K, R87W, R91P were found to be highly pathogenic by both SIFT, PolyPhen2 were further functionally characterized using I-Mutant 2.0, Consurf, MutPred and Project Hope. The findings of the study can be used for prioritizing mutations in the context of genetic studies.

Genetics of atrial fibrillation-an update of recent findings.

Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. AF has a strong genetic predisposition. This review highlights the recent findings on the genetics of AF from genome-wide association studies (GWAS) and high-throughput sequencing studies. The consensus from GWAS implies that AF is both polygenic and pleiotropic in nature. With the advent of whole-genome sequencing and whole-exome sequencing, rare variants associated with AF pathogenesis have been identified. The recent studies have contributed towards better understanding of AF pathogenesis.

Recent technologies enhancing the clinical utility of circulating tumor DNA.

Circulating tumor DNA (ctDNA) is a promising blood based biomarker that is set to revolutionize cancer management. Non-invasive biopsy takes precedence over tissue biopsy for enabling longitudinal monitoring, providing a comprehensive profile of tumor heterogeneity and the ease of repeated sampling. Advanced genomic technologies enable real-time disease monitoring, detect minimal residual disease and recurrence at the earliest stages, the potential time points when treatment significantly reduces morbidity and mortality and enable tailored and personalized therapy. The review highlights evidence from literature that make ctDNA a potential liquid biopsy marker and the clinical utility of the recent techniques that leverage up on ctDNA.

Resequencing CYP2D6 gene in Indian population: CYP2D6*41 identified as the major reduced function allele.

Aim: The CYP2D6 gene is highly polymorphic and harbors population specific alleles that define its predominant metabolizer phenotype. This study aimed to identify polymorphisms in Indian population owing to scarcity of CYP2D6 data in this population. Materials & methods: The CYP2D6 gene was resequenced in 105 south Indians using next generation sequencing technology and haplotypes were reconstructed. Results & conclusion: Four novel missense variants have been designated as CYP2D6*110, *111, *112 and *113. The most common alleles were CYP2D6*1 (42%), *2 (32%), and *41 (12.3%) and diplotypes were CYP2D6*1/*2 (26%), *1/*1 (11%), *2/*41 (10%) and *1/*41 (7%) accounting for high incidence of extensive metabolizers in Indians.

Serotonin transporter gene (SLC6A4) polymorphisms are associated with response to fluoxetine in south Indian major depressive disorder patients.

PURPOSE: Up to 30-40 % of the major depressive disorder patients do not respond sufficiently to antidepressant treatment. Genetic variations in the serotonin transporter gene have been implicated in modulating treatment response to selective serotonin reuptake inhibitors, and this association is influenced by ethnicity. We investigated the influence of serotonin transporter gene variants 5-HTTLPR and rs25531 in Indian population on fluoxetine response. METHODS: One hundred and two major depressive disorder patients were started on fluoxetine treatment and after 6 weeks, classified as responders (n = 56) and non-responders (n = 46) using Hamilton depression rating scale and genotyped. Fisher's exact test was used to compare genotype frequencies between responders and non-responders. One-way analysis of variance and student t test were used to compare the percentage reduction (week 0-6) in Hamilton depression rating scores between genotype and haplotype groups. RESULTS: We observed a significant association between LL genotype of 5-HTTLPR and fluoxetine treatment response (p = 0.0066, OR (95 %) = 4.0 (1.45-11.03)) but not with the functional groups of 5-HTTLPR -rs25531. However, there was a significant difference in percentage reduction in HAM-D scores (week 0-6) between 5-HTTLPR genotypes (LL vs. LS + SS, p = 0.0036; LL vs. LS, p = 0.0109) as well as the functionally grouped haplotypes of 5-HTTLPR -rs25531 (LALA carriers vs. non-carriers of LALA, p = 0.0118; LALA vs. LAS+ LALG, p = 0.0419). CONCLUSION: The LL genotype and LALA haplotype of SLC6A4 are associated with favorable treatment response to fluoxetine in south Indian major depression patients.

Evaluation of interleukin-6 and serotonin as biomarkers to predict response to fluoxetine.

OBJECTIVE: Only 30% of major depressive disorder (MDD) patients achieve complete remission with a serotonergic antidepressant (selective serotonin reuptake inhibitor). We investigated the potential of serotonin (5-HT) and interleukin-6 (IL-6) to serve as functional biomarkers of fluoxetine response. METHODS: Serum IL-6 and 5-HT were measured in 73 MDD patients (39 responders and 34 non-responders) pre- and 6 weeks post-treatment and in 44 normal controls with ELISA. Fluoxetine and norfluoxetine were measured using LC MS/MS. RESULTS: IL-6 levels were significantly higher in MDD patients when compared with controls (p < 0.01), and 5-HT levels were significantly lower in non-responders compared with controls (p = 0.0131). Pre- and post-treatment levels of both biomarkers individually and in combination did not significantly differ between responders and non-responders. Area under the receiver operating characteristics curve for the biomarkers was 0.5. Significant correlation was seen between the percentage change in IL-6 and percentage change in Hamilton Rating Scale for Depression score in responders. Fluoxetine and norfluoxetine concentrations were not significantly different in responders and non-responders, and there was no correlation between fluoxetine concentrations and percentage reduction in 5-HT from week 0 to 6. CONCLUSION: 5-HT and IL-6 may not serve as useful markers of response to fluoxetine because of inconsistent results across different studies. Copyright © 2016 John Wiley & Sons, Ltd.