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Human Mutation

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https://www.readbyqxmd.com/read/28512778/cagi4-crohn-s-exome-challenge-marker-snp-versus-exome-variant-models-for-assigning-risk-of-crohn-disease
#1
Lipika R Pal, Kunal Kundu, Yizhou Yin, John Moult
Understanding the basis of complex trait disease is a fundamental problem in human genetics. The CAGI Crohn's Exome challenges are providing insight into the adequacy of current disease models by requiring participants to identify which of a set of individuals has been diagnosed with the disease, given exome data. For the CAGI4 round, we developed a method that used the genotypes from exome sequencing data only to impute the status of Genome Wide Association Studies (GWAS) marker single nucleotide polymorphisms (SNPs)...
May 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/28512758/reporting-practices-for-unsolicited-and-secondary-findings-from-next-generation-sequencing-technologies-perspectives-of-laboratory-personnel
#2
Danya F Vears, Karine Sénécal, Pascal Borry
While next generation sequencing has enormous potential to identify genetic causes of disease, the nature of the technology means that it can also identify additional information about the individual receiving sequencing that is unrelated to the original rationale for testing. Reporting these unsolicited findings (UF) to clinicians, and subsequently to patients, could lead to potentially lifesaving interventions. Most international guidelines provide limited specific recommendations as to whether these UF should be reported...
May 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/28512736/cagi4-sickkids-clinical-genomes-challenge-a-pipeline-for-identifying-pathogenic-variants
#3
Lipika R Pal, Kunal Kundu, Yizhou Yin, John Moult
Compared with earlier more restricted sequencing technologies, identification of rare disease variants using whole genome sequence has the possibility of finding all causative variants, but issues of data quality and an overwhelming level of background variants complicate the analysis. The CAGI4 SickKids clinical genome challenge provided an opportunity to assess the landscape of variants found in a difficult set of 25 unsolved rare disease cases. To address the challenge, we developed a three-stage pipeline, first carefully analyzing data quality, then classifying high quality gene specific variants into seven categories, and finally examining each candidate variant for compatibility with the often complex phenotypes of these patients for final prioritization...
May 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/28508593/missense-variant-pathogenicity-predictors-generalize-well-across-a-range-of-function-specific-prediction-challenges
#4
Vikas Pejaver, Sean D Mooney, Predrag Radivojac
The steady advances in machine learning and accumulation of biomedical data have contributed to the development of numerous computational models that assess the impact of missense variants. Different methods, however, operationalize impact differently. Two common tasks in this context are the prediction of the pathogenicity of variants and the prediction of their effects on a protein's function. These are related but distinct problems and it is unclear whether methods developed for one are optimized for the other...
May 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/28503910/post-zygotic-single-nucleotide-mosaicisms-contribute-to-the-etiology-of-autism-spectrum-disorder-and-autistic-traits-and-the-origin-of-mutations
#5
Yanmei Dou, Xiaoxu Yang, Ziyi Li, Sheng Wang, Zheng Zhang, Adam Yongxin Ye, Linlin Yan, Changhong Yang, Qixi Wu, Jiarui Li, Boxun Zhao, August Yue Huang, Liping Wei
The roles and characteristics of post-zygotic single-nucleotide mosaicisms (pSNMs) in autism spectrum disorders (ASD) remain unclear. In this study of the whole-exomes of 2,321 families in the Simons Simplex Collection (SSC), we identified 1,248 putative pSNMs in children and 285 de novo SNPs in children with detectable parental mosaicism. Ultra-deep amplicon resequencing suggested a validation rate of 51%. Analyses of validated pSNMs revealed that missense/loss-of-function (LoF) pSNMs with a high mutant allele fraction (MAF> = 0...
May 14, 2017: Human Mutation
https://www.readbyqxmd.com/read/28497574/protein-destabilization-and-loss-of-protein-protein-interaction-are-fundamental-mechanisms-in-cbla-type-methylmalonic-aciduria
#6
Tanja Plessl, Céline Bürer, Seraina Lutz, Wyatt W Yue, Matthias R Baumgartner, D Sean Froese
Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin, generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations...
May 12, 2017: Human Mutation
https://www.readbyqxmd.com/read/28497567/determination-of-disease-phenotypes-and-pathogenic-variants-from-exome-sequence-data-in-the-cagi-4-gene-panel-challenge
#7
Kunal Kundu, Lipika R Pal, Yizhou Yin, John Moult
The use of gene panel sequence for diagnostic and prognostic testing is now widespread, but there are so far few objective tests of methods to interpret these data. We describe the design and implementation of a gene panel sequencing data analysis pipeline (VarP) and its assessment in a CAGI4 community experiment. The method was applied to clinical gene panel sequencing data of 106 patients, with the goal of determining which of 14 disease classes each patient has and the corresponding causative variant(s)...
May 12, 2017: Human Mutation
https://www.readbyqxmd.com/read/28497564/no-significant-enrichment-of-rare-functionally-defective-cpa1-variants-in-a-large-chinese-idiopathic-chronic-pancreatitis-cohort
#8
Hao Wu, Dai-Zhan Zhou, Dorottya Berki, Andrea Geisz, Wen-Bin Zou, Xiao-Tian Sun, Liang-Hao Hu, Zhen-Hua Zhao, An-Jing Zhao, Lin He, David N Cooper, Claude Férec, Jian-Min Chen, Zhao-Shen Li, Miklós Sahin-Tóth, Zhuan Liao
Rare functionally defective carboxypeptidase A1 (CPA1) variants have been reported to predispose to nonalcoholic chronic pancreatitis, mainly the idiopathic subtype. However, independent replication has so far been lacking, particularly in Asian cohorts where initial studies employed small sample sizes. Herein we performed targeted next-generation sequencing of the CPA1 gene in 1112 Han Chinese idiopathic chronic pancreatitis (ICP) patients - the largest ICP cohort so far analyzed in a single population - and 1580 controls...
May 12, 2017: Human Mutation
https://www.readbyqxmd.com/read/28493438/deficient-activity-of-alanyl-trna-synthetase-underlies-an-autosomal-recessive-syndrome-of-progressive-microcephaly-hypomyelination-and-epileptic-encephalopathy
#9
Tojo Nakayama, Jiang Wu, Patricia Galvin-Parton, Jody Weiss, Mary R Andriola, R Sean Hill, Dylan Vaughan, Malak El-Quessny, Brenda J Barry, Jennifer N Partlow, A James Barkovich, Jiqiang Ling, Ganeshwaran H Mochida
Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth (CMT) disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy and spasticity...
May 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28493397/a-recurrent-de-novo-mutation-in-actg1-causes-isolated-ocular-coloboma
#10
Joe Rainger, Kathleen A Williamson, Dinesh C Soares, Julia Truch, Dominic Kurian, Gabriele Gillessen-Kaesbach, Anne Seawright, James Prendergast, Mihail Halachev, Ann Wheeler, Lynn McTeir, Andrew C Gill, Veronica van Heyningen, Megan G Davey, David R FitzPatrick
Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole exome sequencing was used to analyse twelve trios (child affected with OC and both unaffected parents), This identified de novo mutations in ten different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1 and LCP1. Proband-only whole exome sequencing identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p...
May 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28493373/the-novel-%C3%AE-b-crystallin-cryab-mutation-p-d109g-causes-restrictive-cardiomyopathy
#11
Andreas Brodehl, Anna Gaertner-Rommel, Bärbel Klauke, Simon Andre Grewe, Ilona Schirmer, Andreas Peterschröder, Lothar Faber, Matthias Vorgerd, Jan Gummert, Dario Anselmetti, Uwe Schulz, Lech Paluszkiewicz, Hendrik Milting
Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next-generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB-Crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle...
May 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28493391/haplotype-reference-consortium-panel-practical-implications-of-imputations-with-large-reference-panels
#12
Adriana I Iglesias, Sven J van der Lee, Pieter W M Bonnemaijer, René Höhn, Abhishek Nag, Puya Gharahkhani, Anthony P Khawaja, Linda Broer, Paul J Foster, Christopher J Hammond, Pirro G Hysi, Elisabeth M van Leeuwen, Stuart MacGregor, David A Mackey, Johanna Mazur, Stefan Nickels, André G Uitterlinden, Caroline C W Klaver, Najaf Amin, Cornelia M van Duijn
Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, i.e., 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio (VCDR), a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations...
May 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28489339/de-novo-igf2-mutation-on-the-paternal-allele-in-a-patient-with-silver-russell-syndrome-and-ectrodactyly
#13
Kaori Yamoto, Hirotomo Saitsu, Norio Nakagawa, Hisakazu Nakajima, Tatsuji Hasegawa, Yasuko Fujisawa, Masayo Kagami, Maki Fukami, Tsutomu Ogata
Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long-PCR product harboring the mutation and methylation sensitive SmaI and SalI sites before and after SmaI/SalI digestion...
May 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28489284/mapping-genotype-phenotype-associations-of-nssnps-in-coiled-coil-oligomerization-domains-of-the-human-proteome
#14
Kaavya A Mohanasundaram, Mani P Grover, Tamsyn M Crowley, Andrzej Goscinski, Merridee A Wouters
We assessed the impact of disease mutations versus polymorphisms in coiled-coil domains in Uniprot by modelling the structural and functional impact of variants in silico with the coiled-coil prediction program Multicoil. The structural impact of variants was evaluated with respect to three main metrics: the oligomerization score-to determine if the variant is stabilising or destabilising, the oligomerization state, and the register-specific score. The functional impact was queried indirectly in several ways...
May 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28488385/the-c-797-g-a-p-r266k-cystathionine-%C3%AE-synthase-mutation-causes-homocystinuria-by-affecting-protein-stability
#15
Sapna Gupta, Liqun Wang, Warren D Kruger
Mutations in the cystathionine beta-synthase (CBS) gene are the cause of classical homocystinuria, the most common inborn error in sulfur metabolism. The c.797 G>A (p.R266K) mutation in CBS was originally described in several Norwegian pyridoxine responsive CBS deficient patients, and heterologous gene expression studies have shown that the protein has near wild-type levels of enzyme activity. Here, we characterize a transgenic mouse lacking endogenous Cbs and expressing p.R266K human CBS protein from a zinc inducible metallothionein promoter (Tg-R266K Cbs-/-)...
May 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28477385/in-vitro-recapitulation-of-the-site-specific-editing-to-wild-type-of-mutant-ids-mrna-transcripts-and-characterization-of-ids-protein-translated-from-the-edited-mrnas
#16
Susanna Lualdi, Genny Del Zotto, Olga Zegarra-Moran, Nicoletta Pedemonte, Fabio Corsolini, Maurizio Bruschi, Valeria Tomati, Giulia Amico, Giovanni Candiano, Andrea Dardis, David N Cooper, Mirella Filocamo
The transfer of genomic information into the primary RNA sequence can be altered by RNA editing. We have previously shown that genomic variants can be RNA-edited to wild-type. The presence of distinct 'edited' IDS mRNA-transcripts ex vivo evidenced the correction of a nonsense and frameshift variant, respectively, in three unrelated Hunter syndrome patients. This phenomenon was confirmed in various patient samples by a variety of techniques, and quantified by single nucleotide primer extension. Western blotting also confirmed the presence of IDS protein similar in size to the wild-type...
May 6, 2017: Human Mutation
https://www.readbyqxmd.com/read/28471515/critical-points-for-an-accurate-human-genome-analysis
#17
REVIEW
Stefan J White, Jeroen F J Laros, Egbert Bakker, Anne Cambon-Thomsen, Martin Eden, Samantha Leonard, Hanns Lochmüller, Gert Matthijs, Christopher Mattocks, Simon Patton, Katherine Payne, Hans Scheffer, Erica Souche, Ellen Thomassen, Rachel Thompson, Jan Traeger-Synodinos, Steven Van Vooren, Bart Janssen, Johan T den Dunnen
Next-generation sequencing is radically changing how DNA diagnostic laboratories operate. What started as a single-gene profession is now developing into gene panel sequencing and whole exome and genome sequencing (WES/WGS) analyses. With further advances in sequencing technology and concomitant price reductions, whole genome sequencing (WGS) will soon become the standard and be routinely offered. Here we focus on the critical steps involved in performing WGS, with a particular emphasis on points where WGS differs from WES, the important variables that should be taken into account, and the quality control measures that can be taken to monitor the process...
May 4, 2017: Human Mutation
https://www.readbyqxmd.com/read/28459139/exploring-the-limits-of-the-usefulness-of-mutagenesis-in-studies-of-allosteric-mechanisms
#18
Qingling Tang, Aileen Y Alontaga, Todd Holyoak, Aron W Fenton
The outcome of structure-guided mutational analyses are often used in support of postulated mechanisms of protein allostery. However, the limits of how informative mutations can be in understanding allosteric mechanisms are not completely clear. Here, we report an exercise to evaluate if mutational data can support a simplistic mechanistic model, developed with minimal data inputs. Due to the lack of a mechanism to explain how alanine allosterically modifies the affinity of human liver pyruvate kinase (hL-PYK; approved symbol PKLR) for its substrate, phosphoenolpyruvate (PEP), we proposed a speculative allosteric mechanism for this system...
April 29, 2017: Human Mutation
https://www.readbyqxmd.com/read/28449315/panelcn-mops-copy-number-detection-in-targeted-ngs-panel-data-for-clinical-diagnostics
#19
Gundula Povysil, Antigoni Tzika, Julia Vogt, Verena Haunschmid, Ludwine Messiaen, Johannes Zschocke, Günter Klambauer, Sepp Hochreiter, Katharina Wimmer
Targeted next-generation-sequencing (NGS) panels have largely replaced Sanger sequencing in clinical diagnostics. They allow for the detection of copy-number variations (CNVs) in addition to single-nucleotide variants and small insertions/deletions. However, existing computational CNV detection methods have shortcomings regarding accuracy, quality control (QC), incidental findings, and user-friendliness. We developed panelcn.MOPS, a novel pipeline for detecting CNVs in targeted NGS panel data. Using data from 180 samples, we compared panelcn...
April 27, 2017: Human Mutation
https://www.readbyqxmd.com/read/28444810/large-differences-in-proportions-of-harmful-and-benign-amino-acid-substitutions-between-proteins-and-diseases
#20
Gerard C P Schaafsma, Mauno Vihinen
Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbour the largest proportion of harmful variants (42...
April 25, 2017: Human Mutation
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