Project description:The identification of the genetic risk factors in patients with isolated cleft palate by whole genome sequencing analysis. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results are relevant to routine genetic counselling practice and genetic testing recommendations.
Project description:Whole exome sequencing was performed on set of 48 DNA samples obtained from 16 EGFR mutated NSCLC patients whose tumors progressed following EGFR-TKI treatment. The DNA samples included baseline biopsy, rebiopsy and blood from the same patient. By comparing the variants in rebiopsy tumors and baseline tumors we aim to understand the genomic alterations responsible for the development of EGFR-TKI resistance in NSCLC patients.
Project description:Of the multiple anatomical sites represented in oral cancer, squamous cell carcinoma of the tongue (TSCC) shows the highest incidence among younger age group. Chewing betel leaf, areca nut & slaked lime and smoking tobacco are common practises in India which have direct clinical implication in TSCC carcinogenesis. Here, for the first time we define the landscape of genomic alterations in TSCC from the Indian diaspora which would help to identify novel therapeutic targets for clinical intervention and define the genetic basis for TSCC. We performed high throughput sequencing of fifty four tongue samples using whole exome sequencing (n=47, 23 paired normal tumor and 1 unpaired) and transcriptome sequencing (n=17, 10 tumor and 5 normal). Mutation, copy number analysis were carried out using exome sequencing data and transcriptome analysis provided expressed genes and transcript fusions in tongue cancer patients. Further, integrated analysis were performed to identify biologically relevant alterations. Our preliminary analysis revealed presence of most frequently altered mutations in TSCC which includes mutations in TP53, NOTCH1, CDKN2A, USP6, KMT2D etc, consistent with literature. We observed high frequency of CG/T(GC/A) transversions in non-CpG islands, a signature associated with tobacco exposure. Somatic copy number analysis revealed copy number gain in known hallmarks such as CCND1, MYC, ORAOV1 genes along with copy number alteration in novel genes. Significant positive correlation was observed in the genes harbouring copy number gains and showing increased expression.
Project description:Younger age and VTE recurrence are more likely to be caused by genetic risk factors than secondary VTE in older patients who more likely have comorbidities. When the exome rare variant genotyping database of the Scripps VTE Registry for adults < 55 yrs old was generated and analyzed for single nucleotide polymorphisms (SNPs). Two F5 related SNPs (rs6025, factor V Leiden and rs6687813) exceeded significance (FDR (false discovery rate) p < 0.05). No other variants met genome-wide significance. When the data for the subgroup of cases with recurrent VTE that are more likely to have genetic risk factors than cases with a single VTE episode were compared to controls (N=211 controls and N=32 recurrent VTE cases), 28 SNPs, including the F5 rs6025 SNP, achieved significance (FDR p < 0.05).
Project description:Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variant found in patients, but not those found exclusively in controls, impair suppression of IRF and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Project description:To efficiently identify genetic susceptibility variants for gastric cancer, including rare coding variants, we performed an exome chip-based array study. We found that a linkage disequilibrium (LD) block containing 2 significant variants in PSCA gene increased the risk and two blocks that included 15 suggested variants including TRIM31, TRIM 40, TRIM 10, and TRIM26 regions, and included one suggested variant and OR2H2 gene showed protective associations with gastric cancer susceptibility. In addition, the PLEC region (rs200893203), FBLN2 region (rs201192415), and EPHA2 region (rs3754334) were associated with increased susceptibility
Project description:We used the whole exome sequencing to analyze the off-target effect of base editing system in mouse genomic DNA, which was extracted from haploid stem cells, mouse tails of semi-cloned embryos and mutant pups. The purpose of this sequencing is to find whether there exists off-target effect in the genome. By obtaining over 100 million reads of each sample from WES, we mapped the reads to the reference data base (mm10) and calculated the numbers of SNVs and indels. After filtering out naturally-occurring variants in the SNP database (dbSNP) and excluding SNPs also found in the wild-type genome, we next compared the DNA sequences at the remaining SNP sites with the on-target sequence. The results indicated that rare off-targets events happened in tested cell and embryos.