Showing papers by "Soma Das published in 2015"
TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
17,834 citations
University of Zaragoza1, University of Pennsylvania2, Children's Hospital of Philadelphia3, University of Edinburgh4, University of Chicago5, University of Lübeck6, University of Milan7, Odense University Hospital8, Spanish National Research Council9, Leiden University10, University of California, San Francisco11, James Cook University Hospital12, Boston Children's Hospital13, Cincinnati Children's Hospital Medical Center14, Southern General Hospital15, Radboud University Nijmegen Medical Centre16, Greater Baltimore Medical Center17, Linköping University18, University of Milano-Bicocca19, Children's Hospital of Eastern Ontario20, University of Texas at San Antonio21, Great Ormond Street Hospital22, UCL Institute of Child Health23, Mount Sinai Hospital, Toronto24, University of Toronto25, Centre for Addiction and Mental Health26, National University of Río Cuarto27, Karolinska Institutet28, Drexel University29, University of Amsterdam30
TL;DR: It is confirmed that de novo SMC3 mutations account for ∼1%–2% of CdLS‐like phenotypes, and modeling of the mutation effects on protein structure suggests a dominant‐negative effect on the multimeric cohesin complex.
Abstract: Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximate to 1%-2% of CdLS-like phenotypes.
66 citations
TL;DR: The findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers and Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.
Abstract: Purpose: VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors. Experimental Design: We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy. Results: rs34231037 (C482R) in KDR , the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance ( P = 2.7 × 10 −37 ). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size ( P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib ( P = 0.01). Conclusion: Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors. Clin Cancer Res; 21(2); 365–72. ©2014 AACR .
32 citations
TL;DR: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidated.
Abstract: Background: Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro ; however, little is known about their roles in vivo .
Methods: Within UGT1A1 , UGT1A4 , UGT1A9 , UGT2B7 , UGT2B10 , and UGT2B17 , 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2 . The association between variation in these UGTs and glucuronidation activity within European and African American current smokers ( n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3′-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.
Results: Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans ( P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine ( P = 0.008–0.04) and cotinine ( P = <0.001–0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans ( P = 0.01, P < 0.001). UGT2B17*2 ( P = 0.03) in European Americans and UGT2B7 variants ( P = 0.02–0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A ( P = 0.007–0.01), UGT2B10 ( P = 0.02), and UGT2B7 ( P = 0.02–0.03) variants in African Americans were nominally associated with NNAL glucuronidation.
Conclusions: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo , in particular UGT2B10 and cotinine glucuronidation.
Impact: Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94–104. ©2014 AACR .
29 citations
TL;DR: Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced Rars2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS1 promoter are likely to represent a new causal mechanism of PCH6.
Abstract: Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5'-UTR of the RARS2 gene in the homozygous state. This variant was identified through next-generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6.
29 citations
TL;DR: The results confirmed that CDK5RAP2 causes microcephaly and MCPH causes developmental delay and speech delay, and the once-in-a-lifetime therapy is recommended to correct these problems.
Abstract: Keywords:
autosomal recessive primary microcephaly (MCPH);
CDK5RAP2;
microcephaly;
developmental delay;
speech delay;
failure to thrive
5 citations
TL;DR: This study demonstrates the effectiveness of using NGS technology to identify patients with a hereditary predisposition to hematologic malignancies using a panel of 76 genes associated with IBMFS and/or familial MDS/AL.
2 citations