Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria

CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post- transplant serum creatinine when compared to “Gold Standard” clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD) kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008). Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future

Staging quality is related to the survival of women with endometrial cancer: a Scottish population based study.Deficient surgical staging and omission of adjuvant radiotherapy is associated with poorer survival of women diagnosed with endometrial cancer in Scotland during 1996 and 1997

The association between treatment variation and survival of women with endometrial cancer was investigated. A retrospective cohort based upon the complete Scottish population registered on in-patient and day-case hospital discharge data (Scottish Morbidity Record-1) and cancer registration (Scottish Morbidity Record-6) coded C54 and C55 in ICD10, between 1st January 1996 to 31st December 1997 were analysed. Seven hundred and three patients who underwent surgical treatment out of 781 patients that were diagnosed with endometrial cancer in Scotland during 1996 and 1997. The overall quality of surgical staging was poor. The quality of staging was related to both the year that the surgeon passed the Member of the Royal College of Obstetricians and Gynaecologists examination and also to ‘specialist’ status but was not related to surgeon caseload. Two clinically important prognostic factors were found to be associated with survival; whether the International Federation of Obstetrics and Gynaecology stage was documented, RHR=2.0 (95% CI=1.3 to 3.1) and also to the use of adjuvant radiotherapy, RHR=2.2 (95% CI=1.5 to 3.5). The associations with survival were strongest in patients with advanced disease, International Federation of Obstetrics and Gynaecology stages 1C through to stage 3. Deficiencies in staging and variations in the use of adjuvant radiotherapy represent a possible source of avoidable mortality in patients with endometrial cancer. Consequently, there should be a greater emphasis on improving the overall quality of surgical staging in endometrial cancer

In silico genotyping of the maize nested association mapping population

Nested Association Mapping (NAM) has been proposed as a means to combine the power of linkage mapping with the resolution of association mapping. It is enabled through sequencing or array genotyping of parental inbred lines while using low-cost, low-density genotyping technologies for their segregating progenies. For purposes of data analyses of NAM populations, parental genotypes at a large number of Single Nucleotide Polymorphic (SNP) loci need to be projected to their segregating progeny. Herein we demonstrate how approximately 0.5 million SNPs that have been genotyped in 26 parental lines of the publicly available maize NAM population can be projected onto their segregating progeny using only 1,106 SNP loci that have been genotyped in both the parents and their 5,000 progeny. The challenge is to estimate both the genotype and genetic location of the parental SNP genotypes in segregating progeny. Both challenges were met by estimating their expected genotypic values conditional on observed flanking markers through the use of both physical and linkage maps. About 90%, of 500,000 genotyped SNPs from the maize HapMap project, were assigned linkage map positions using linear interpolation between the maize Accessioned Gold Path (AGP) and NAM linkage maps. Of these, almost 70% provided high probability estimates of genotypes in almost 5,000 recombinant inbred lines

A single amino acid substitution in ORF1 dramatically decreases L1 retrotransposition and provides insight into nucleic acid chaperone activity

L1 is a ubiquitous interspersed repeated sequence in mammals that achieved its high copy number by autonomous retrotransposition. Individual L1 elements within a genome differ in sequence and retrotransposition activity. Retrotransposition requires two L1-encoded proteins, ORF1p and ORF2p. Chimeric elements were used to map a 15-fold difference in retrotransposition efficiency between two L1 variants from the mouse genome, TFC and TFspa, to a single amino acid substitution in ORF1p, D159H. The steady-state levels of L1 RNA and protein do not differ significantly between these two elements, yet new insertions are detected earlier and at higher frequency in TFC, indicating that it converts expressed L1 intermediates more effectively into new insertions. The two ORF1 proteins were purified and their nucleic acid binding and chaperone activities were examined in vitro. Although the RNA and DNA oligonucleotide binding affinities of these two ORF1 proteins were largely indistinguishable, D159 was significantly more effective as a nucleic acid chaperone than H159. These findings support a requirement for ORF1p nucleic acid chaperone activity at a late step during L1 retrotransposition, extend the region of ORF1p that is known to be critical for its functional interactions with nucleic acids, and enhance understanding of nucleic acid chaperone activity

Altered sirtuin expression is associated with node-positive breast cancer

Sirtuins are genes implicated in cellular and organismal ageing. Consequently, they are speculated to be involved in diseases of ageing including cancer. Various cancers with widely differing prognosis have been shown to have differing and characteristic expression of these genes; however, the relationship between sirtuin expression and cancer progression is unclear. In order to correlate cancer progression and sirtuin expression, we have assessed sirtuin expression as a function of primary cell ageing and compared sirtuin expression in normal, ‘nonmalignant' breast biopsies to breast cancer biopsies using real-time polymerase chain reaction (PCR). Levels of SIRT7 expression were significantly increased in breast cancer (P<0.0001). Increased levels of SIRT3 and SIRT7 transcription were also associated with node-positive breast cancer (P<0.05 and P<0.0001, respectively). This study has demonstrated differential sirtuin expression between nonmalignant and malignant breast tissue, with consequent diagnostic and therapeutic implications

Improved breast cancer survival following introduction of an organized mammography screening program among both screened and unscreened women: a population-based cohort study

Introduction: Mammography screening reduces breast cancer mortality through earlier diagnosis but may convey further benefit if screening is associated with optimized treatment through multidisciplinary medical care. In Norway, a national mammography screening program was introduced among women aged 50 to 69 years during 1995/6 to 2004. Also during this time, multidisciplinary breast cancer care units were implemented. Methods: We constructed three cohorts of breast cancer patients: 1) the pre-program group comprising women diagnosed and treated before mammography screening began in their county of residence, 2) the post-program group comprising women diagnosed and treated through multidisciplinary breast cancer care units in their county but before they had been invited to mammography screening; and 3) the screening group comprising women diagnosed and treated after invitation to screening. We calculated Kaplan-Meier plots and multivariable Cox proportional hazard models. Results: We studied 41,833 women with breast cancer. The nine-year breast cancer-specific survival rate was 0.66 (95%CI: 0.65 to 0.67) in the pre-program group; 0.72 (95%CI: 0.70 to 0.74) in the post-program group; and 0.84 (95%CI: 0.80 to 0.88) in the screening group. In multivariable analyses, the risk of death from breast cancer was 14% lower in the post-program group than in the pre-program group (hazard ratio 0.86; (95%CI: 0.78 to 0.95, P = 0.003)). Conclusions: After nine years follow-up, at least 33% of the improved survival is attributable to improved breast cancer management through multidisciplinary medical care

Newborn Sequencing in Genomic Medicine and Public Health

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening

Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Paclitaxel is a microtubule-stabilizing drug that has been commonly used in treating cancer. Due to genetic heterogeneity within patient populations, therapeutic response rates often vary. Here we used the NCI60 panel to identify SNPs associated with paclitaxel sensitivity. Using the panel's GI50 response data available from Developmental Therapeutics Program, cell lines were categorized as either sensitive or resistant. PLINK software was used to perform a genome-wide association analysis of the cellular response to paclitaxel with the panel's SNP-genotype data on the Affymetrix 125 k SNP array. FastSNP software helped predict each SNP's potential impact on their gene product. mRNA expression differences between sensitive and resistant cell lines was examined using data from BioGPS. Using Haploview software, we investigated for haplotypes that were more strongly associated with the cellular response to paclitaxel. Ingenuity Pathway Analysis software helped us understand how our identified genes may alter the cellular response to paclitaxel.</p> <p>Results</p> <p>43 SNPs were found significantly associated (FDR < 0.005) with paclitaxel response, with 10 belonging to protein-coding genes (<it>CFTR</it>, <it>ROBO1</it>, <it>PTPRD</it>, <it>BTBD12</it>, <it>DCT</it>, <it>SNTG1</it>, <it>SGCD</it>, <it>LPHN2</it>, <it>GRIK1</it>, <it>ZNF607</it>). SNPs in <it>GRIK1</it>, <it>DCT</it>, <it>SGCD </it>and <it>CFTR </it>were predicted to be intronic enhancers, altering gene expression, while SNPs in <it>ZNF607 </it>and <it>BTBD12 </it>cause conservative missense mutations. mRNA expression analysis supported these findings as <it>GRIK1</it>, <it>DCT</it>, <it>SNTG1</it>, <it>SGCD </it>and <it>CFTR </it>showed significantly (p < 0.05) increased expression among sensitive cell lines. Haplotypes found in <it>GRIK1, SGCD, ROBO1, LPHN2</it>, and <it>PTPRD </it>were more strongly associated with response than their individual SNPs.</p> <p>Conclusions</p> <p>Our study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel.</p