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Human Mutation

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https://www.readbyqxmd.com/read/28432734/monogenic-diabetes-syndromes-locus-specific-databases-for-alstr%C3%A3-m-wolfram-and-thiamine-responsive-megaloblastic-anaemia
#1
Dewi Astuti, Ataf Sabir, Piers Fulton, Malgorzata Zatyka, Denise Williams, Carol Hardy, Gabriella Milan, Francesca Favaretto, Patrick Yu-Wai-Man, Julia Rohayem, Miguel López de Heredia, Tamara Hershey, Lisbeth Tranebjaerg, Jian-Hua Chen, Annabel Chaussenot, Virginia Nunes, Bess Marshall, Susan McAfferty, Vallo Tillmann, Pietro Maffei, Veronique Paquis-Flucklinger, Tarekign Geberhiwot, Wojciech Mlynarski, Kay Parkinson, Virginie Picard, Gema Esteban Bueno, Renuka Dias, Amy Arnold, Caitlin Richens, Richard Paisey, Fumi Urano, Robert Semple, Richard Sinnott, Timothy G Barrett
We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström and Thiamine-responsive megaloblastic anaemia syndromes respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1...
April 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/28432706/varied-pathological-and-therapeutic-response-effects-associated-with-chchd2-mutant-and-risk-variants
#2
Murni Tio, Rujing Wen, Yih Lin Lim, Zul Haikhel Bin Zukifli, Shaoping Xie, Patrick Ho, Zhidong Zhou, Tong-Wey Koh, Yi Zhao, Eng-King Tan
Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction which could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress and impairment in synaptic transmission...
April 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/28419606/stratified-polygenic-risk-prediction-model-with-application-to-cagi-bipolar-disorder-sequencing-data
#3
Maggie Haitian Wang, Billy Chang, Rui Sun, Inchi Hu, Xiaoxuan Xia, William Ka Kei Wu, Ka Chun Chong, Benny Chung-Ying Zee
Genetic data consists of a wide range of marker types, including common, low frequency, and rare variants. Multiple genetic markers and their interactions play central roles in the heritability of complex disease. In this study, we propose an algorithm that uses a stratified variable selection design by genetic architectures and interaction effects, achieved by a data-set adaptive W-test. The polygenic sets in all strata were integrated to form a classification rule. The algorithm was applied to the Critical Assessment of Genome Interpretation 4 bipolar challenge sequencing data...
April 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/28419628/hla-hd-an-accurate-hla-typing-algorithm-for-next-generation-sequencing-data
#4
Shuji Kawaguchi, Koichiro Higasa, Masakazu Shimizu, Ryo Yamada, Fumihiko Matsuda
The accurate typing of HLA alleles is critical for a variety of medical applications, such as genomic studies of multifactorial diseases, including immune system and inflammation-related disorders, and donor selection in organ transplantation and regenerative medicine. Here we developed a new algorithm for determining HLA alleles using next-generation sequencing (NGS) results. The method consists of constructing an extensive dictionary of HLA alleles, precise mapping of the NGS reads, and calculating a score based on weighted read counts to select the most suitable pair of alleles...
April 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/28409863/the-influence-of-snp-based-chromosomal-microarray-and-nipt-on-the-diagnostic-yield-in-10-000-fetuses-with-and-without-fetal-ultrasound-anomalies
#5
Malgorzata I Srebniak, Maarten F C M Knapen, Marike Polak, Marieke Joosten, Karin E M Diderich, Lutgarde C P Govaerts, Marjan Boter, Joan N R Kromosoeto, Daniella Aloysia C M van Hassel, Gido Huijbregts, Wilfred F J van Ijcken, Roger Heydanus, Anneke Dijkman, Toon Toolenaar, Femke A T de Vries, Jeroen Knijnenburg, Attie T J I Go, Robert-Jan H Galjaard, Diane Van Opstal
Prenatal diagnostics has been impacted by technological changes in the past decade, which have affected the diagnostic yield. The aim of this study was to evaluate the impact of SNP array and non-invasive prenatal testing (NIPT) on the diagnostic yield and the number of invasive tests in our center. The frequency of pathogenic fetal unbalanced chromosome aberrations was studied in 10,005 cases referred for prenatal testing in 2009-2015. Chromosomal SNP microarray analysis replaced karyotyping in all invasively tested pregnancies and since 2014 a choice between NIPT and diagnostic testing with microarray was offered to women with an increased risk for common aneuploidy...
April 14, 2017: Human Mutation
https://www.readbyqxmd.com/read/28407397/whole-protein-alanine-scanning-mutagenesis-of-allostery-a-large-percentage-of-a-protein-can-contribute-to-mechanism
#6
Qingling Tang, Aron W Fenton
Many studies of allosteric mechanisms use limited numbers of mutations to test whether residues play "key" roles. However, if a large percentage of the protein contributes to allosteric function, mutating any residue would have a high probability of modifying allostery. Thus, a predicted mechanism that is dependent on only a few residues could erroneously appear to be supported. We used whole-protein alanine-scanning mutagenesis to determine which amino acid side-chains of human liver pyruvate kinase (hL-PYK; approved symbol PKLR) contribute to regulation by fructose-1,6-bisphosphate (activator) and alanine (inhibitor)...
April 13, 2017: Human Mutation
https://www.readbyqxmd.com/read/28397319/damold-a-data-mining-platform-for-variant-annotation-and-visualization-in-molecular-diagnostics-research
#7
Ram Vinay Pandey, Stephan Pabinger, Albert Kriegner, Andreas Weinhäusel
Next-Generation Sequencing (NGS) has become a powerful and efficient tool for routine mutation screening in clinical research. As each NGS test yields hundreds of variants, the current challenge is to meaningfully interpret the data and select potential candidates. Analyzing each variant while manually investigating several relevant databases to collect specific information is a cumbersome and time-consuming process, and it requires expertise and familiarity with these databases. Thus, a tool that can seamlessly annotate variants with clinically relevant databases under one common interface would be of great help for variant annotation, cross-referencing, and visualization...
April 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28397312/3lessons-from-the-cagi-4-hopkins-clinical-panel-challenge
#8
John-Marc Chandonia, Aashish Adhikari, Marco Carraro, Aparna Chhibber, Garry R Cutting, Yao Fu, Alessandra Gasparini, David T Jones, Andreas Kramer, Kunal Kundu, Hugo Y K Lam, Emanuela Leonardi, John Moult, Lipika R Pal, David B Searls, Sohela Shah, Shamil Sunyaev, Silvio C E Tosatto, Yizhou Yin, Bethany A Buckley
The CAGI-4 Hopkins clinical panel challenge was an attempt to assess state of the art methods for clinical phenotype prediction from DNA sequence. Participants were provided with exonic sequences of 83 genes for 106 patients from the Johns Hopkins DNA Diagnostic Laboratory. Five groups participated in the challenge, predicting both the probability that each patient had each of fourteen possible classes of disease, as well as one or more causal variants. In cases where the Hopkins laboratory reported a variant, at least one predictor correctly identified the disease class in 36 of 43 patients (84%)...
April 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28397307/genetic-variants-in-micrornas-and-their-binding-sites-within-gene-3-utrs-associate-with-susceptibility-to-age-related-macular-degeneration-amd
#9
Mohsen Ghanbari, Stefan J Erkeland, Lei Xu, Johanna M Colijn, Oscar H Franco, Abbas Dehghan, Caroline C W Klaver, Magda A Meester-Smoor
Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease that results from multiple genetic and environmental factors. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate target mRNAs and are frequently implicated in human diseases. Here, we investigated the association of genetic variants in miRNAs and miRNA-binding sites within gene 3'UTRs with AMD using data from the largest AMD genome-wide association study. First, we identified three variants in miRNAs significantly associated with AMD...
April 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28390077/aberrant-hras-transcript-processing-underlies-a-distinctive-phenotype-within-the-rasopathy-clinical-spectrum
#10
Francesca Pantaleoni, Dorit Lev, Ion C Cirstea, Marialetizia Motta, Francesca Romana Lepri, Lisabianca Bottero, Serena Cecchetti, Ilan Linger, Stefano Paolacci, Elisabetta Flex, Antonio Novelli, Alessandra Carè, Reza Ahmadian, Emilia Stellacci, Marco Tartaglia
RASopathies are a group of rare, clinically related conditions affecting development and growth, and are caused by germline mutations in genes encoding signal transducers and modulators with a role in the RAS signaling network. These disorders share facial dysmorphia, short stature, variable cognitive deficits, skeletal and cardiac defects, and a variable predisposition to malignancies. Here, we report on a de novo 10-nucleotide-long deletion in HRAS (c.481_490delGGGACCCTCT, NM_176795.4; p.Leu163ProfsTer52, NP_789765...
April 8, 2017: Human Mutation
https://www.readbyqxmd.com/read/28378423/detecting-pkd1-variants-in-polycystic-kidney-disease-patients-by-single-molecule-long-read-sequencing
#11
Daniel M Borràs, Rolf Vossen, Michael Liem, Henk P J Buermans, Hans Dauwerse, Dave van Heusden, Ron T Gansevoort, Johan T den Dunnen, Bart Janssen, Dorien J M Peters, Monique Losekoot, Seyed Yahya Anvar
A genetic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is challenging due to allelic heterogeneity, high GC-content, and homology of the PKD1 gene with six pseudogenes. Short-read next-generation sequencing (NGS) approaches, such as whole genome (WGS) and whole exome sequencing (WES), often fail at reliably characterizing complex regions such as PKD1. However, long-read single-molecule sequencing has been shown to be an alternative strategy that could overcome PKD1 complexities and discriminate between homologous regions of PKD1 and its pseudogenes...
April 4, 2017: Human Mutation
https://www.readbyqxmd.com/read/28370826/microtubule-associated-defects-caused-by-efhc1-mutations-in-juvenile-myoclonic-epilepsy
#12
Praveen K Raju, Parthasarthy Satishchandra, Sourav Nayak, Vishwanathan Iyer, Sanjib Sinha, Anuranjan Anand
Juvenile myoclonic epilepsy (JME) is a common form of epilepsy with a substantial genetic basis to its etiology. While earlier studies have identified EFHC1 as a causative gene for JME, subsequent studies have suggested that ethnicity may play a role in determining expression of the JME phenotype among individuals carrying EFHC1 mutations. Here, we report on our studies on EFHC1 in JME patients from India. We examined the complete structure of the EFHC1 transcript from 480 JME patients and 700 control chromosomes by direct sequencing...
March 31, 2017: Human Mutation
https://www.readbyqxmd.com/read/28370845/benchmarking-predictions-of-allostery-in-liver-pyruvate-kinase-in-cagi4
#13
Qifang Xu, Qingling Tang, Panagiotis Katsonis, Olivier Lichtarge, David Jones, Samuele Bovo, Giulia Babbi, Pier L Martelli, Rita Casadio, Gyu Rie Lee, Chaok Seok, Aron W Fenton, Roland L Dunbrack
Critical Assessment of Genome Interpretation "CAGI" is a global community experiment to objectively assess computational methods for predicting phenotypic impacts of genomic variation. One of the 2015-2016 competitions focused on predicting the influence of mutations on the allosteric regulation of human liver pyruvate kinase. More than 30 different researchers accessed the challenge data. However, only four groups accepted the challenge. Features used for predictions ranged from evolutionary constraints, mutant site locations relative to active and effector binding sites, and computational docking outputs...
March 29, 2017: Human Mutation
https://www.readbyqxmd.com/read/28337824/phenotype-genotype-correlations-of-pigo-deficiency-with-variable-phenotypes-from-infantile-lethality-to-mild-learning-difficulties
#14
Junpei Tanigawa, Haruka Mimatsu, Seiji Mizuno, Nobuhiko Okamoto, Daisuke Fukushi, Koji Tominaga, Hiroyuki Kidokoro, Yukako Muramatsu, Eriko Nishi, Shota Nakamura, Daisuke Motooka, Noriko Nomura, Kiyoshi Hayasaka, Tetsuya Niihori, Yoko Aoki, Shin Nabatame, Masahiro Hayakawa, Jun Natsume, Keiichi Ozono, Taroh Kinoshita, Nobuaki Wakamatsu, Yoshiko Murakami
Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency...
March 23, 2017: Human Mutation
https://www.readbyqxmd.com/read/28332257/exomic-variants-of-an-elderly-cohort-of-brazilians-in-the-abraom%C3%A2-database
#15
Michel Satya Naslavsky, Guilherme Lopes Yamamoto, Tatiana Ferreira de Almeida, Suzana A M Ezquina, Daniele Yumi Sunaga, Nam Pho, Daniel Bozoklian, Tatiana Orli Milkewitz Sandberg, Luciano Abreu Brito, Monize Lazar, Danilo Vicensotto Bernardo, Edson Amaro, Yeda A O Duarte, Maria Lúcia Lebrão, Maria Rita Passos-Bueno, Mayana Zatz
Brazilians are highly admixed with ancestry from Europe, Africa, America, and Asia yet still underrepresented in genomic databanks. We hereby present a collection of exomic variants from 609 elderly Brazilians in a census-based cohort (SABE609) with comprehensive phenotyping. Variants were deposited in ABraOM (Online Archive of Brazilian Mutations), a web-based public database. Population representative phenotype and genotype repositories are essential for variant interpretation through allele frequency filtering; since elderly individuals are less likely to harbor pathogenic mutations for early and adult-onset diseases, such variant databases are of great interest...
March 23, 2017: Human Mutation
https://www.readbyqxmd.com/read/28326637/purinergic-receptors-p2rx4-and-p2rx7-in-familial-multiple-sclerosis
#16
A Dessa Sadovnick, Ben J Gu, Anthony L Traboulsee, Cecily Q Bernales, Mary Encarnacion, Irene M Yee, Maria G Criscuoli, Xin Huang, Amber Ou, Carol J Milligan, Steven Petrou, James S Wiley, Carles Vilariño-Güell
Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility to multiple sclerosis (MS). In this study, we set out to evaluate whether rare coding variants of major effect could also be identified in these purinergic receptors. Sequencing analysis of P2RX4 and P2RX7 in 193 MS patients and 100 controls led to the identification of a rare three variant haplotype (P2RX7 rs140915863:C>T [p.T205M], P2RX7 rs201921967:A>G [p.N361S], and P2RX4 rs765866317:G>A [p.G135S]) segregating with disease in a multi-incident family with six family members diagnosed with MS (logarithm of odds = 3...
March 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/28317323/a-functional-snp-regulated-by-mir-196a-3p-in-the-3-utr-of-fgf2-is-associated-with-bone-mineral-density-in-the-chinese-population
#17
Dong-Li Zhu, Yan Guo, Yan Zhang, Shan-Shan Dong, Wen Xu, Ruo-Han Hao, Xiao-Feng Chen, Han Yan, Shui-Yun Yang, Tie-Lin Yang
Previous studies have identified FGF2 as a susceptibility gene for osteoporosis in Caucasians. Evaluating the genetic associations in different ethnicities is necessary. Moreover, elucidating the functional mechanism for the susceptibility loci is important to offer new targets for therapeutic studies. Here, we genotyped 10 SNPs in FGF2 and tested for associations with bone mineral density (BMD) in a discovery sample of 1,300 Chinese subjects. Nominally significant results were subjected to replication in another sample of 1,039 Chinese subjects...
March 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/28276201/rare-deleterious-variants-in-grhl3-are-associated-with-human-spina-bifida
#18
Philippe Lemay, Patrizia De Marco, Alexandre Emond, Dan Spiegelman, Alexandre Dionne-Laporte, Sandra Laurent, Elisa Merello, Andrea Accogli, Guy A Rouleau, Valeria Capra, Zoha Kibar
Neural tube defects (NTDs), including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a re-sequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida...
March 8, 2017: Human Mutation
https://www.readbyqxmd.com/read/28271586/single-base-substitutions-in-the-chm-promoter-as-a-cause-of-choroideremia
#19
Alina Radziwon, Gavin Arno, Dianna Wheaton, Ellen M McDonagh, Emma L Baple, Kaylie Webb-Jones, David Birch, Andrew R Webster, Ian M MacDonald
Although over 150 unique mutations affecting the coding sequence of CHM have been identified in patients with the X-linked chorioretinal disease choroideremia (CHM), no regulatory mutations have been reported, and indeed the promoter has not been defined. Here we describe two independent families affected by CHM bearing a mutation outside the gene's coding region at position c.-98: C>A and C>T, which segregated with the disease. The male proband of family 1 was found to lack CHM mRNA and its gene product Rab escort protein 1 (REP-1), while whole genome sequencing of an affected male in family 2 excluded the involvement of any other known retinal genes...
March 8, 2017: Human Mutation
https://www.readbyqxmd.com/read/28256047/maternal-mutations-of-foxf1-cause-alveolar-capillary-dysplasia-despite-not-being-imprinted
#20
Miguel Alsina Casanova, Ana Monteagudo-Sánchez, Luciana Rodiguez Guerineau, Franck Court, Isabel Gazquez Serrano, Loreto Martorell, Carlota Rovira Zurriaga, Gudrun E Moore, Miho Ishida, Montserrat Castañon, Elisenda Moliner Calderon, David Monk, Julio Moreno Hernando
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare cause of pulmonary hypertension in newborns. Maternally inherited point mutations in Forkhead Box F1 gene (FOXF1), deletions of the gene, or its long-range enhancers on the maternal allele are responsible for this neonatal lethal disorder. Here, we describe monozygotic twins and one full-term newborn with ACD and gastrointestinal malformations caused by de novo mutations of FOXF1 on the maternal-inherited alleles. Since this parental transmission is consistent with genomic imprinting, the parent-of-origin specific monoallelic expression of genes, we have undertaken a detailed analysis of both allelic expression and DNA methylation...
March 3, 2017: Human Mutation
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