Apert's syndrome: Study by whole exome sequencing.

In the present study we attempted a parent-child trio, whole exome sequencing (WES) approach to study Apert's syndrome. Clinical characteristics of the child were noted down and WES was carried out using Ion Torrent System that revealed the presence of previously reported P253R mutation in FGFR2 gene. Presence of two SNPs rs1047057 and rs554851880 in FGFR2 gene with an allelic frequency of 0.5113 and 0.001176 respectively and 161 complete damaging mutations were found. This study is the first reported case of exome sequencing approach on an Apert's syndrome patient aimed at providing better genetic counselling in a non-consanguineous relationship.

Research advances in Apert syndrome.

Apert syndrome is one of the several genetic syndromes associated with craniosynostosis, a condition that includes premature fusion of one or multiple cranial sutures. There has been significant clinical variation among different sutural synostoses and also within particular suture synostosis. Enormous progress has been made in identifying various mutations associated with Apert Syndrome. Although a causal gene has been defined, the precise role of this mutation in producing craniofacial dysmorphology and other related abnormalities is in the process of discovery. Most of the understanding regarding this rare disorder has been possible due to mouse models that have helped in deciphering the elements of this rare human disease. Thus, molecular and cellular understanding of the disease has taken a leap and further with the advent of technology definitive diagnosis of the syndrome is no more of an issue. In this review, we have discussed and consolidated the possible molecular studies that have contributed in understanding of this rare syndrome. This article may help clinicians and researchers to inform about the latest progress in Apert syndrome.

Role of TLR4 (C1196T) and CD14 (C-260T) Polymorphisms in Development of Ischemic Stroke, Its Subtypes and Hemorrhagic Stroke.

In the present study, we evaluated the association of TLR4 and CD14 polymorphisms, i.e. C1196T and C-260T, respectively, with ischemic stroke (n = 700), its subtypes and hemorrhagic stroke (n = 300) in a South Indian population from Telangana. The genotypes were determined using PCR-RFLP, and the strength of association between genotypes and stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. The results revealed a lack of association for TLR4 variant with ischemic stroke and hemorrhagic stroke, although a significant association was observed with the subtypes extracranial large artery (p = 0.008), other determined aetiology (p = 0.03) and undetermined aetiology (p = 0.01). Investigations on the variant of CD14 gene revealed negative association among ischemic stroke patients; however, a significant association was observed for hemorrhagic stroke following dominant and recessive genotypic model (p = 0.05, p = 0.02). Among ischemic stroke subtype, a significant association was observed with intracranial large artery, extracranial large artery, other determined aetiology and undetermined aetiology form of stroke (p < 0.01). Further, analysis of the CD14 variant between the two major stroke types revealed a significant difference in genotype distribution following the co-dominant genotypic model (p = 0.01).

Genetic Understanding of Stroke Treatment: Potential Role for Phosphodiesterase Inhibitors.

Phosphodiesterase (PDE) gene family is a large family having at least 21 genes and multiple versions (isoforms) of the phosphodiesterase enzymes. These enzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and therefore, play a pivotal role in various cellular functions. PDE inhibitors (PDEI) are drugs that block one or more of the five subtypes of the PDE family and thereby prevent inactivation of the intracellular cAMP and cGMP by the respective PDE-subtypes. The first clinical use of PDEI was reported almost three decades ago. Studies later found the ability of these compounds to increase the levels of ubiquitous secondary messenger molecules that can cause changes in vascular tone, cardiac function and other cellular events and thus these findings paved the way for their use in various medical emergencies. PDEs are found to be distributed in many tissues including brain. Therefore, new therapeutic agents in the form of PDEI are being explored in neurodegenerative diseases including stroke. Although studies have revealed their use in cerebral infarction prevention, their full-fledged application in times of neurological emergency or stroke in specific has been very limited so far. Nevertheless, recent investigations suggest PDE4 and PDE5 inhibitors to play a vital role in mitigating stroke symptoms by modulating signaling mechanisms in PDE pathway. Further, extensive research in terms of their pharmacological properties like dosing, drug specific activities, use of simultaneous medications, ancillary properties of these compounds and studies on adverse drug reactions needs to be carried out to set them as standard drugs of use in stroke.

Association of APOE (E2, E3 and E4) gene variants and lipid levels in ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian population.

In the present study we evaluated the association of APOE (E2/E3/E4) polymorphism with ischemic stroke (n=620), its subtypes and hemorrhagic stroke (n=250) in a South Indian population from Telangana. The genotypes were determined using PCR-RFLP while lipid levels were measured using commercially available kits. We found significant difference in the genotypic distribution between hemorrhagic stroke patients and controls for certain genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3; E4/E4 vs.E2/E4 and E3 vs. E4]. However, no significant difference was observed in genotypic distribution between ischemic stroke patients and controls. On analysing the genotypic distribution between ischemic and hemorrhagic stroke patients, statistically significant difference was observed in specific genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3 and E4/E4 vs. E2/E4]. In ischemic stroke subtypes analysing for alleles E3 vs. E2 and E3 vs. E4, we found significant association with intracranial large artery (p=0.01), cardioembolic stroke (p=0.001 and p=0.0004) and lacunar stroke (p=0.02). Analysing the association of various genotypes with different lipid levels significant association was observed for VLDL (P=0.000) and for triglyceride (P=0.000) levels with E2/E4 and E3/E4 genotypes in ischemic stroke but not in hemorrhagic stroke. In conclusion, our results suggest that APOE polymorphism does seem to play a role in hemorrhagic stroke and also in the development of specific subtypes of ischemic stroke. Further, in ischemic stroke VLDL and triglycerides levels were found to be significantly associated with E2/E4 and E3/E4 genotypes.

Primordial dwarfism: overview of clinical and genetic aspects.

Primordial dwarfism is a group of genetic disorders which include Seckel Syndrome, Silver-Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier-Gorlin Syndrome. This genetic disorder group is characterized by intra-uterine growth retardation and post-natal growth abnormalities which occur as a result of disorganized molecular and genomic changes in embryonic stage and, thus, it represents a unique area to study growth and developmental abnormalities. Lot of research has been carried out on different aspects; however, a consolidated review that discusses an overall spectrum of this disorder is not accessible. Recent research in this area points toward important molecular and cellular mechanisms in human body that regulate the complexity of growth process. Studies have emerged that have clearly associated with a number of abnormal chromosomal, genetic and epigenetic alterations that can predispose an embryo to develop PD-associated developmental defects. Finding and associating such fundamental changes to its subtypes will help in re-examination of alleged functions at both cellular and developmental levels and thus reveal the intrinsic mechanism that leads to a balanced growth. Although such findings have unraveled a subtle understanding of growth process, we further require active research in terms of identification of reliable biomarkers for different subtypes as an immediate requirement for clinical utilization. It is hoped that further study will advance the understanding of basic mechanisms regulating growth relevant to human health. Therefore, this review has been written with an aim to present an overview of chromosomal, molecular and epigenetic modifications reported to be associated with different subtypes of this heterogenous disorder. Further, latest findings with respect to clinical and molecular genetics research have been summarized to aid the medical fraternity in their clinical utility, for diagnosing disorders where there are overlapping physical attributes and simultaneously inform about the latest developments in PD biology.

Association between PDE4D gene and ischemic stroke: recent advancements.

Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome.

Draft Genome Sequences of Two Drug-Resistant Isolates of Pseudomonas aeruginosa Obtained from Keratitis Patients in India.

We report here the draft genomes of two drug (fluoroquinolone)-resistant clinical isolates of Pseudomonas aeruginosa obtained from the corneal scrapings of keratitis patients from India. The two annotated genomes are 6.31 Mb and 6.41 Mb in size. These genomes are expected to facilitate the identification and understanding of the genes associated with acquired multidrug resistance.

Genetic determinants in ischaemic stroke subtypes: seven year findings and a review.

Stroke is a global health problem and a leading cause of disability worldwide. There have been numerable studies undertaking research on different aspects of ischaemic stroke employing various epidemiological, clinical and molecular parameters. Nevertheless ischaemic stroke being a complex disorder with different subtypes demands equal attention towards its subtypes too. Since there has been enough evidence that disposition to certain subtype is genetically determined and there is a distinct mechanism that influences its development, association studies should focus on subtypes simultaneously while studying specific genes. Data from such studies will thus provide better and intricate findings with regard to heterogenous ischaemic stroke. In the present review we discuss the genes studied by our group over a period of seven years in association with stroke subtypes in a South Indian population and correlate the findings with similar genetic studies from other populations so as to provide an overview of various genes involved in the pathogenesis of ischaemic stroke subtypes.

Interleukin 1ß (+3954, -511 and -31) polymorphism in chronic periodontitis patients from North India.

OBJECTIVE: Several studies have implicated the role of interleukin-1 in various chronic diseases including periodontitis. The present study was carried out with an aim to evaluate the role of interleukin 1ß polymorphisms, namely +3954C/T, -511C/T and -31T/C, in the development of chronic periodontitis. MATERIALS AND METHODS: Twenty-nine chronic periodontitis patients and 31 healthy controls of North Indian origin from Chhattisgarh were recruited for the study. The genotypes for the three variants were determined using the PCR-RFLP technique and the strength of association between genotypes and periodontitis was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. RESULTS: Analysis for the +3954 allelic and genotypic frequencies of the polymorphism revealed a significant difference in the CT genotype between periodontitits patients and controls (p = 0.03). A significant difference was also observed in the allelic frequencies between the two groups (p = 0.02). For the -511 site, TT genotype revealed a significant association with the disease (p = 0.01). A significant association was also found following the co-dominant model (p = 0.007). However, the -31 polymorphism revealed no significant difference between patients and controls. CONCLUSIONS: In conclusion, the present study suggests a strong association of the TT genotype of -511 and CT genotype of +3954 variant of interleukin 1ß with chronic periodontitis. However, the -31 variant did not show a significant association with the disease.

Association of ACE gene I/D polymorphism and ACE levels with hemorrhagic stroke: comparison with ischemic stroke.

In the present study, we investigated the association of insertion/deletion polymorphism of ACE gene with genetic predisposition to hemorrhagic stroke and also determined the mean ACE activity levels in ischemic and hemorrhagic stroke patients. Two hundred hemorrhagic stroke, 200 ischemic stroke patients and 200 gender and age matched controls were recruited for the study. We found statistically significant difference in the genotypic distribution between hemorrhagic patients and controls for dominant, co-dominant and recessive models. Significant difference was observed in the allelic frequencies between hemorrhagic patients and controls. Multiple logistic regression analysis confirmed these findings [adjusted OR for DD genotype was 2.46 (95 % CI 1.43-4.21) and p = 0.001] and [adjusted OR for ID genotype was 5.45 (95 % CI 2.6-10.4) and p = 0.001]. We have already established the association of this polymorphism in ischemic stroke patients. Comparing hemorrhagic with ischemic stroke, we found a significant difference in genotypic distribution between the two [for II vs. DD, χ (2) = 4.75; p = 0.03, OR = 0.5 (95 % CI 0.27-0.93) and for DD vs. ID, χ (2) = 5.1; p = 0.02, OR = 1.8 (95 % CI 1.1-3.3)]. Our results indicate that DD genotype and D allele are important risk factors for the development of stroke. Individuals harboring DD genotype of ACE I/D polymorphism are more predisposed to hemorrhagic stroke than ischemic stroke. Further, the mean ACE activity level was found to be significantly higher in hemorrhagic and ischemic stroke in comparison with controls, but there was no significant difference in the levels found between the two types of stroke.

Association of -1382A>G CCL11 gene variant with ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian population.

BACKGROUND: CCL11 (Eotaxin-1) is an important inflammatory cytokine belonging to the CC family of chemokines associated with a number of infection or inflammation-related diseases such as atherosclerosis and stroke. We investigated the association of CCL11 gene polymorphism rs4795895-1382A>G with ischemic and hemorrhagic stroke. MATERIALS AND METHODS: Six hundred and twenty ischemic stroke patients, 620 age- and sex-matched healthy controls, and 220 hemorrhagic stroke patients, 220 age- and sex-matched healthy controls were included in the present study. The CCL11 gene polymorphism rs4795895-1382A>G was determined using PCR-RFLP technique. RESULTS: We found a statistically significant difference in the genotypic distribution between ischemic stroke patients and controls (For GG vs. AA, χ² = 7.604; P < 0.001, Odds ratio = 2.793; 95% CI = 1.308-5.9). For GG vs. AA + AG, χ² = 44.8, P < 0.001, Odds ratio = 2.382 (95% CI = 1.842-3.081). A significant difference was observed in the frequency of G and A alleles in patients and controls (For G vs. A, χ² = 43.26; P < 0.001, Odds ratio = 2.127; 95% CI = 1.693-2.672). Statistically significant difference was observed in the genotypic distribution between hemorrhagic stroke patients and controls (For GG vs. AG, χ² = 26.78; P = 0.001, Odds ratio = 3.5; 95% CI = 2.162-5.824). A significant difference was observed in the frequency of G and A alleles in patients and controls (For G vs. A, χ² = 41.98; P = 0.001, Odds ratio = 4.1; 95% CI = 2.61-6.44). CONCLUSION: The results of the present study show that the GG genotype is a significant risk factor for ischemic as well as hemorrhagic stroke. Further, the frequency of the GG genotype was observed to be higher in hemorrhagic stroke patients in comparison with ischemic stroke. Evaluating the association with ischemic stroke subtypes, a significant association was observed with intracranial large artery atherosclerosis and lacunar stroke.

E-selectin gene (S128R) polymorphism in hemorrhagic stroke: comparison with ischemic stroke.

Increasing evidence suggests that genetic variation in inflammatory genes plays a pivotal role in pathogenesis of stroke. The aim of the present study was to evaluate the association of E-selectin S128R polymorphism with hemorrhagic stroke and also to evaluate the genotypic and allelic variation with ischemic stroke in a South Indian population from Andhra Pradesh. In this study, we recruited 250 hemorrhagic stroke patients along with 250 age and sex matched controls. The genotypes were determined using PCR-RFLP method and the strength of association between genotypes and hemorrhagic stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. Allelic and genotypic frequencies of the polymorphism differed significantly between hemorrhagic stroke patients and controls (p<0.001). Significant association was also found following dominant (p<0.001) and co-dominant (p<0.001) models. On comparing the genotypic and allelic frequencies between ischemic and hemorrhagic stroke significant difference was found between the two stroke types (p<0.001). In conclusion, we found the AC genotype to be a significant risk factor for hemorrhagic stroke and we also found significant differences in AC genotype and C allele among the two stroke types. The genotypic and allelic variation between the ischemic and hemorrhagic stroke, suggests that E-selectin S128R mediated amplification of leukocytes onto endothelial cells, leading to secondary damage of brain cells is more pronounced in hemorrhagic stroke.

CRP gene (1059G>C) polymorphism and its plasma levels in ischemic stroke and hemorrhagic stroke in a south Indian population.

In the present study, we evaluated the association of 1059G>C polymorphism in C-reactive protein (CRP) gene with the risk of ischemic and hemorrhagic strokes. We did not find a significant association of this polymorphism with stroke. However, 2 % of mutants were observed in hemorrhagic stroke patients with a 0.01 frequency for the C allele. We also estimated the high-sensitivity C-reactive protein (hsCRP) levels in hemorrhagic stroke and compared the levels with our already published data on ischemic stroke. The hsCRP level in hemorrhagic stroke was found to be significantly elevated in comparison with that in controls (p<0.001). However, there was no difference in the mean value of hsCRP levels between types of stroke. In conclusion, the G>C polymorphism in the promoter region of the CRP gene is not abundant in the population and cannot be connected with different hsCRP levels and stroke prediction. The CRP level is a useful marker in stroke, but cannot help in differentiating between types of stroke.

Association of E-selectin gene polymorphism (S128R) with ischemic stroke and stroke subtypes.

E-selectin is an important inflammatory cytokine involved in the pathogenesis of various diseases such as atherosclerosis and stroke. We investigated the association of E-selectin gene polymorphism (S128R) with ischemic stroke and its subtypes. We studied 610 patients with ischemic stroke and 610 age- and sex-matched healthy controls. The ischemic stroke was classified according to Trial of Org10172 in Acute Stroke Treatment (TOAST). E-selectin gene polymorphism (S128R) was determined by polymerase chain reaction-restriction fragment length polymorphism technique. We found statistically significant difference in the genotypic distribution between patients and controls (for AC vs. AA, χ(2) = 49.5; p < 0.001, odds ratio = 5.47(95 % CI, 3.25-9.21). A significant difference was observed in the frequency of C and A alleles in patients and controls (for C vs. A, χ(2) = 47.4; p < 0.001, odds ratio = 5.13 (95 % CI, 3.06-8.57). Multiple logistic regression analysis revealed that the most predictive risk factor for stroke was AC genotype (adjusted odds ratio = 1.450 (95 % CI, 1.23-2.75) and p = 0.001), hypertension, smoking, and diabetes (p = 0.001 in each case). We also found a significant association of AC genotype with intracranial large artery atherosclerosis (p < 0.01, odds ratio = 9.37, (95 % CI, 5.31-16.5) and small artery occlusion (p < 0.0001, odds ratio = 9.81 (95 % CI, 4.94-19.4). Our results indicate that the individuals bearing AC genotype of E-selectin gene polymorphism (S128R) are more prone to stroke than AA genotype.