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Human Mutation

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https://www.readbyqxmd.com/read/29775997/improved-acmg-compliant-in-silico-prediction-of-pathogenicity-for-missense-substitutions-encoded-by-tp53-variants
#1
Cristina Fortuno, Paul A James, Erin L Young, Bing Feng, Magali Olivier, Tina Pesaran, Sean V Tavtigian, Amanda B Spurdle
Clinical interpretation of germline missense variants represents a major challenge, including those in the TP53 Li-Fraumeni syndrome gene. Bioinformatic prediction is a key part of variant classification strategies. We aimed to optimize the performance of the Align-GVGD tool used for p53 missense variant prediction, and compare its performance to other bioinformatic tools (SIFT, PolyPhen-2) and ensemble methods (REVEL, BayesDel). Reference sets of assumed pathogenic and assumed benign variants were defined using functional and/or clinical data...
May 18, 2018: Human Mutation
https://www.readbyqxmd.com/read/29774626/analysis-of-intra-tumor-heterogeneity-in-neurofibromatosis-type-1-plexiform-neurofibromas-and-neurofibromas-with-atypical-features-correlating-histological-and-genomic-findings
#2
Meritxell Carrió, Bernat Gel, Ernest Terribas, Adriana Carolina Zucchiatti, Teresa Moliné, Inma Rosas, Álex Teulé, Santiago Ramón Y Cajal, Juan Carlos López-Gutiérrez, Ignacio Blanco, Elisabeth Castellanos, Conxi Lázaro, Anat Stemmer-Rachamimov, Cleofé Romagosa, Eduard Serra
Plexiform neurofibromas (PNFs) are benign peripheral nerve sheath tumors involving large nerves present in 30-50% Neurofibromatosis type 1 (NF1) patients. Atypical neurofibromas (ANF) are distinct nodular lesions with atypical features on histology that arise from PNFs. The risk and timeline of malignant transformation in ANF is difficult to assess. A recent NIH workshop has stratified ANFs and separated a subgroup with multiple atypical features and higher risk of malignant transformation termed atypical neurofibromatous neoplasms with uncertain biological potential (ANNUBP)...
May 17, 2018: Human Mutation
https://www.readbyqxmd.com/read/29768694/de-novo-variants-in-rhobtb2-an-atypical-rho-gtpase-gene-cause-epileptic-encephalopathy
#3
Hazrat Belal, Mitsuko Nakashima, Hiroshi Matsumoto, Kenji Yokochi, Mariko Taniguchi-Ikeda, Kazushi Aoto, Mohammed Badrul Amin, Azusa Maruyama, Hiroaki Nagase, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Kazumoto Iijima, Shigeaki Nonoyama, Naomichi Matsumoto, Hirotomo Saitsu
By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin/proteasome complex...
May 16, 2018: Human Mutation
https://www.readbyqxmd.com/read/29766597/a-functional-assay-for-the-clinical-annotation-of-genetic-variants-of-uncertain-significance-in-diamond-blackfan-anemia
#4
Anna Aspesi, Marta Betti, Marika Sculco, Chiara Actis, Cristina Olgasi, Marcin W Wlodarski, Adrianna Vlachos, Jeffrey M Lipton, Ugo Ramenghi, Claudio Santoro, Antonia Follenzi, Steven R Ellis, Irma Dianzani
Diamond-Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss-of-function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in-frame indels...
May 15, 2018: Human Mutation
https://www.readbyqxmd.com/read/29749045/evidence-for-galnt12-as-a-moderate-penetrance-gene-for-colorectal-cancer
#5
Daniel R Evans, Srividya Venkitachalam, Leslie Revoredo, Amanda T Dohey, Erica Clarke, Julia J Pennell, Amy E Powell, Erina Quinn, Lakshmeswari Ravi, Thomas A Gerken, Jane S Green, Michael O Woods, Kishore Guda
Characterizing moderate penetrance susceptibility genes is an emerging frontier in colorectal cancer (CRC) research. GALNT12 is a strong candidate CRC-susceptibility gene given previous linkage and association studies, and inactivating somatic and germline alleles in CRC patients. Previously, we found rare segregating germline GALNT12 variants in a clinic-based cohort (N = 118) with predisposition for CRC. Here, we screened a new population-based cohort of incident CRC cases (N = 479) for rare (MAF ≤1%) deleterious germline GALNT12 variants...
May 10, 2018: Human Mutation
https://www.readbyqxmd.com/read/29737001/clinical-and-functional-characterization-of-two-novel-zbtb20-mutations-causing-primrose-syndrome
#6
Emilia Stellacci, Katharina Steindl, Pascal Joset, Laura Mercurio, Massimiliano Anselmi, Serena Cecchetti, Laura Gogoll, Markus Zweier, Annette Hackenberg, Gianfranco Bocchinfuso, Lorenzo Stella, Marco Tartaglia, Anita Rauch
Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders...
May 7, 2018: Human Mutation
https://www.readbyqxmd.com/read/29726087/asthma-and-allergic-rhinitis-associate-with-the-rs2229542-variant-that-induces-a-p-lys90glu-mutation-and-compromises-akr1b1-protein-levels
#7
Elena García-Martín, Francisco J Sánchez-Gómez, Gemma Amo, Jesús García Menaya, Concepción Cordobés, Pedro Ayuso, M Carmen Plaza Serón, Miguel Blanca, Paloma Campo, Gara Esguevillas, María A Pajares, José A G Agúndez, Dolores Pérez-Sala
Asthma and rhinitis are two of the main clinical manifestations of allergy, in which increased reactive oxygen or electrophilic species can play a pathogenic role. Aldose reductase (AKR1B1) is involved in aldehyde detoxification and redox balance. Recent evidence from animal models points to a role of AKR1B1 in asthma and rhinitis, but its involvement in human allergy has not been addressed. Here, the putative association of allergic rhinitis and asthma with AKR1B1 variants has been explored by analysis of single-strand variants on the AKR1B1 gene sequence in 526 healthy subjects and 515 patients with allergic rhinitis, 366 of whom also had asthma...
May 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29726066/partial-loss-of-function-of-sodium-channel-scn8a-in-familial-isolated-myoclonus
#8
Jacy L Wagnon, Niccolò E Mencacci, Bryan S Barker, Eric R Wenger, Kailash P Bhatia, Bettina Balint, Miryam Carecchio, Nicholas W Wood, Manoj K Patel, Miriam H Meisler
Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment...
May 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29726057/mutations-and-common-variants-in-the-human-arginase-1-arg1-gene-impact-on-patients-diagnostic-and-protein-structure-considerations
#9
Carmen Diez-Fernandez, Véronique Rüfenacht, Corinne Gemperle, Ralph Fingerhut, Johannes Häberle
The urea cycle disorder argininemia is caused by a defective arginase 1 (ARG1) enzyme resulting from mutations in the ARG1 gene. Patients generally develop hyperargininemia, spastic paraparesis, progressive neurological and intellectual impairment and persistent growth retardation. Interestingly, in contrast to other urea cycle disorders, hyperammonemia is rare. We report here 66 mutations (12 of which are novel), including 30 missense mutations, 7 nonsense, 10 splicing, 15 deletions, two duplications, one small insertion and one translation initiation codon mutation...
May 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29704307/mecp2-variation-in-rett-syndrome-an-overview-of-current-coverage-of-genetic-and-phenotype-data-within-existing-databases
#10
Gillian S Townend, Friederike Ehrhart, Henk J van Kranen, Mark Wilkinson, Annika Jacobsen, Marco Roos, Egon L Willighagen, David van Enckevort, Chris T Evelo, Leopold M G Curfs
Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases it results from a loss of function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counselling for parents...
April 27, 2018: Human Mutation
https://www.readbyqxmd.com/read/29696747/marker-chromosome-genomic-structure-and-temporal-origin-implicate-a-chromoanasynthesis-event-in-a-family-with-pleiotropic-psychiatric-phenotypes
#11
Christopher M Grochowski, Shen Gu, Bo Yuan, Julia Tcw, Kristen J Brennand, Jonathan Sebat, Dheeraj Malhotra, Shane McCarthy, Uwe Rudolph, Anna Lindstrand, Zechen Chong, Deborah L Levy, James R Lupski, Claudia M B Carvalho
Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed 3 duplications and 3 triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis-like event...
April 25, 2018: Human Mutation
https://www.readbyqxmd.com/read/29696744/ngs-testing-for-cardiomyopathy-utility-of-adding-rasopathy-associated-genes
#12
Ozge Ceyhan-Birsoy, Maya M Miatkowski, Elizabeth Hynes, Birgit H Funke, Heather Mason-Suares
RASopathies include a group of syndromes caused by pathogenic germline variants in RAS-MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal anomalies. Recently, variants in RASopathy-associated genes have been reported in individuals with apparently non-syndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy-associated genes to cardiomyopathy panels, we tested 11 RASopathy-associated genes by next generation sequencing (NGS), including NGS-based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM)...
April 25, 2018: Human Mutation
https://www.readbyqxmd.com/read/29696732/seshat-a-web-service-for-accurate-annotation-validation-and-analysis-of-tp53-variants-generated-by-conventional-and-next-generation-sequencing
#13
Tuomas Tikkanen, Bernard Leroy, Jean Louis Fournier, Rosa Ana Risques, Jitka Malcikova, Thierry Soussi
Accurate annotation of genomic variants in human diseases is essential to allow personalized medicine. Assessment of somatic and germline TP53 alterations has now reached the clinic and is required in several circumstances such as the identification of the most effective cancer therapy for patients with chronic lymphocytic leukemia (CLL). Here we present Seshat, a web service for annotating TP53 information derived from sequencing data. A flexible framework allows the use of standard file formats such as Mutation Annotation Format (MAF) or Variant Call Format (VCF), as well as common TXT files...
April 25, 2018: Human Mutation
https://www.readbyqxmd.com/read/29691940/novel-cask-mutations-in-cases-with-syndromic-microcephaly
#14
Francesca Cristofoli, Koen Devriendt, Erica E Davis, Hilde Van Esch, Joris R Vermeesch
Mutations in CASK cause a wide spectrum of phenotypes in humans ranging from mild X-linked intellectual disability to a severe microcephaly (MC) and pontocerebellar hypoplasia syndrome. Nevertheless, predicting pathogenicity and phenotypic consequences of novel CASK mutations through the exclusive consideration of genetic information and population-based data remains a challenge. Using whole exome sequencing, we identified four novel CASK mutations in individuals with syndromic MC. To understand the functional consequences of the different point mutations on the development of MC and cerebellar defects we established a transient loss of function zebrafish model, and demonstrate recapitulation of relevant neuroanatomical phenotypes...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29691939/genome-sequencing-reveals-a-novel-genetic-mechanism-underlying-dihydropyrimidine-dehydrogenase-deficiency-a-novel-missense-variant-c-1700g-a-and-a-large-intragenic-inversion-in-dpyd-spanning-intron-8-to-intron-12
#15
André B P van Kuilenburg, Maja Tarailo-Graovac, Judith Meijer, Britt Drogemoller, Jerry Vockley, Dirk Maurer, Doreen Dobritzsch, Colin J Ross, Wyeth Wasserman, Rutger Meinsma, Lida Zoetekouw, Clara D M van Karnebeek
Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with a variable clinical presentation. A family with three DPD deficient patients presented with unusual clinical phenotypes including pregnancy-induced symptoms, transient visual impairment, severe developmental delay, cortical blindness and delayed myelination in the brain. DPYD Sanger sequencing showed heterozygosity for the c.1905+1G > A mutation and a novel missense variant c.1700G > A (p.G456E). The recombinantly-expressed p.G456E DPD variant showed increased temperature lability probably caused by structural rearrangements within the DPD protein...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29689137/insight-into-vitamin-b-6-dependent-epilepsy-due-to-plpbp-previously-prosc-missense-mutations
#16
Lorena Tremiño, Alicia Forcada-Nadal, Vicente Rubio
Vitamin B6 -dependent genetic epilepsy was recently associated to mutations in PLPBP (previously PROSC), the human version of the widespread COG0325 gene that encodes TIM-barrel-like pyridoxal phosphate (PLP)-containing proteins of unclear function. We produced recombinantly, purified and characterized human PROSC (called now PLPHP) and its six missense mutants reported in epileptic patients. Normal PLPHP is largely a monomer with PLP bound through a Schiff-base linkage. The PLP-targeting antibiotic D-cycloserine decreased the PLP-bound peak as expected for pseudo-first-order reaction...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29688601/de-novo-mutations-in-the-set-nuclear-proto-oncogene-encoding-a-component-of-the-inhibitor-of-histone-acetyltransferases-inhat-complex-in-patients-with-non-syndromic-intellectual-disability
#17
Servi Jc Stevens, Vyne van der Schoot, Magalie S Leduc, Tuula Rinne, Seema R Lalani, Marjan M Weiss, Johanna M van Hagen, Augusta Ma Lachmeijer, Sylvia G Stockler-Ipsiroglu, Anna Lehman, Han G Brunner
The role of disturbed chromatin remodelling in the pathogenesis of intellectual disability (ID) is well established and illustrated by de novo mutations found in a plethora of genes encoding for proteins of the epigenetic regulatory machinery. We describe mutations in the "SET nuclear proto-oncogene" (SET), encoding a component of the "inhibitor of acetyltransferases" (INHAT) complex, involved in transcriptional silencing. Using whole exome sequencing, four patients were identified with de novo mutations in the SET gene...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29688594/whole-genome-sequencing-in-patients-with-ciliopathies-uncovers-a-novel-recurrent-tandem-duplication-in-ift140
#18
Véronique Geoffroy, Corinne Stoetzel, Sophie Scheidecker, Elise Schaefer, Isabelle Perrault, Séverine Bär, Ariane Kröll, Marion Delbarre, Manuela Antin, Anne-Sophie Leuvrey, Charline Henry, Hélène Blanché, Eva Decker, Katja Kloth, Günter Klaus, Christoph Mache, Dominique Martin-Coignard, Steven McGinn, Anne Boland, Jean-François Deleuze, Sylvie Friant, Sophie Saunier, Jean-Michel Rozet, Carsten Bergmann, Hélène Dollfus, Jean Muller
Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases such as the Bardet-Biedl syndrome. Using whole genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27 to 30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole exome sequencing...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29664219/unusual-association-of-a-unique-cag-interruption-in-5-of-dm1-ctg-repeats-with-intergenerational-contractions-and-low-somatic-mosaicism
#19
Tome Stéphanie, Dandelot Elodie, Dogan Céline, Bertrand Alexis, Genevieve David, Pereon Yann, Simon Marie, Bonnefont Jean-Paul, Bassez Guillaume, Gourdon Geneviève
Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions...
April 17, 2018: Human Mutation
https://www.readbyqxmd.com/read/29663568/abnormal-function-of-the-uba5-protein-in-a-case-of-early-developmental-and-epileptic-encephalopathy-with-suppression-burst
#20
Cécile Mignon-Ravix, Mathieu Milh, Charlotte Sophia Kaiser, Jens Daniel, Florence Riccardi, Pierre Cacciagli, Majdi Nagara, Tiffany Busa, Eva Liebau, Laurent Villard
Early myoclonic epilepsy (EME) or Aicardi syndrome is one of the most severe epileptic syndromes affecting neonates. We performed whole exome sequencing in a sporadic case affected by EME and his parents. In the proband, we identified a homozygous missense variant in the ubiquitin-like modifier activating enzyme 5 (UBA5) gene, encoding a protein involved in post-translational modifications. Functional analysis of the UBA5 variant protein reveals that it is almost completely unable to perform its trans-thiolation activity...
April 16, 2018: Human Mutation
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