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Human Mutation

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https://www.readbyqxmd.com/read/29330883/genotype-phenotype-correlations-in-individuals-with-pathogenic-rere-variants
#1
Valerie K Jordan, Brieana Fregeau, Xiaoyan Ge, Jessica Giordano, Ronald J Wapner, Tugce B Balci, Melissa T Carter, John A Bernat, Amanda N Moccia, Anshika Srivastava, Donna M Martin, Stephanie L Bielas, John Pappas, Melissa D Svoboda, Marlène Rio, Nathalie Boddaert, Vincent Cantagrel, Andrea M Lewis, Fernando Scaglia, Jennefer N Kohler, Jonathan A Bernstein, Annika M Dries, Jill A Rosenfeld, Colette DeFilippo, Willa Thorson, Yaping Yang, Elliott H Sherr, Weimin Bi, Daryl A Scott
Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies and sensorineural hearing loss when compared to loss-of-function variants that are likely to lead to haploinsufficiency...
January 13, 2018: Human Mutation
https://www.readbyqxmd.com/read/29330893/mitogenomic-differences-between-the-normal-and-tumour-cells-of-colorectal-cancer-patients
#2
Katarzyna Skonieczna, Boris Malyarchuk, Arkadiusz Jawień, Andrzej Marszałek, Zbigniew Banaszkiewicz, Paweł Jarmocik, Tomasz Grzybowski
So far, a reliable spectrum of mitochondrial DNA mutations in colorectal cancer cells is still unknown, and neither is their significance in carcinogenesis. Indeed, it remains debatable whether mtDNA mutations are "drivers" or "passengers" of colorectal carcinogenesis. Thus, we analyzed 200 mitogenomes from normal and cancer tissues of 100 colorectal cancer patients. Minority variant mutations were detected at the 1% level. We showed that somatic mutations frequently occur in colorectal cancer cells (75%) and are randomly distributed across the mitochondrial genome...
January 12, 2018: Human Mutation
https://www.readbyqxmd.com/read/29327391/molecular-phenotype-of-slc4a11-missense-mutants-setting-the-stage-for-personalized-medicine-in-corneal-dystrophies
#3
Kumari Alka, Joseph R Casey
SLC4A11 mutations cause cases of congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (HS), and Fuchs endothelial corneal dystrophy (FECD). Defective water reabsorption from corneal stroma by corneal endothelial cells (CECs) leads to these corneal dystrophies. SLC4A11, in the CEC basolateral membrane facilitates transmembrane movement of H2 O, NH3 and H+ -equivalents. Some SLC4A11 disease mutants have impaired folding, leading to a failure to move to the cell surface, which in some cases can be corrected by the drug, Glafenine...
January 11, 2018: Human Mutation
https://www.readbyqxmd.com/read/29316027/somatic-mutations-activating-wiskott-aldrich-syndrome-protein-concomitant-with-ras-pathway-mutations-in-juvenile-myelomonocytic-leukemia-patients
#4
A Coppe, L Nogara, M S Pizzuto, A Cani, S Cesaro, R Masetti, F Locatelli, G Te Kronnie, G Basso, S Bortoluzzi, S Bresolin
The WAS gene product is expressed exclusively in the cytoplasm of hematopoietic cells and constitutional genetic abrogation of WASP leads to Wiskott-Aldrich syndrome (WAS). Moreover, mutational activation of WASP has been associated with X-linked neutropenia (XLN). Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present Juvenile MyeloMonocytic Lukemia (JMML)-like features, confounding differential diagnosis above all in the co-presence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients...
January 7, 2018: Human Mutation
https://www.readbyqxmd.com/read/29314435/mutation-update-of-transcription-factor-genes-foxe3-hsf4-maf-and-pitx3-causing-cataracts-and-other-developmental-ocular-defects
#5
Deepti Anand, Smriti A Agrawal, Anne Slavotinek, Salil A Lachke
Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in non-ocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented...
January 4, 2018: Human Mutation
https://www.readbyqxmd.com/read/29314548/clinical-biochemical-and-genetic-features-associated-with-vars2-related-mitochondrial-disease
#6
Francesco Bruni, Ivano Di Meo, Emanuele Bellacchio, Bryn D Webb, Robert McFarland, Zofia M A Chrzanowska-Lightowlers, Langping He, Ewa Skorupa, Isabella Moroni, Anna Ardissone, Anna Walczak, Henna Tyynismaa, Pirjo Isohanni, Hanna Mandel, Holger Prokisch, Tobias Haack, Penelope E Bonnen, Bertini Enrico, Ewa Pronicka, Daniele Ghezzi, Robert W Taylor, Daria Diodato
In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy...
January 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29297947/loss-of-function-mutations-in-isca2-disrupt-4fe-4s-cluster-machinery-and-cause-a-fatal-leukodystrophy-with-hyperglycinemia-and-mtdna-depletion
#7
Joseph T Alaimo, Arnaud Besse, Charlotte L Alston, Ki Pang, Vivek Appadurai, Monisha Samanta, Patroula Smpokou, Robert McFarland, Robert W Taylor, Penelope E Bonnen
Iron-sulfur (Fe-S) clusters are essential co-factors for proteins that participate in fundamental cellular processes including metabolism, DNA replication and repair, transcriptional regulation, and the mitochondrial electron transport chain (ETC). ISCA2 plays a role in the biogenesis of Fe-S clusters and a recent report described subjects displaying infantile-onset leukodystrophy due to bi-allelic mutation of ISCA2. We present two additional unrelated cases, and provide a more complete clinical description that includes hyperglycinemia, leukodystrophy of the brainstem with longitudinally extensive spinal cord involvement, and mtDNA deficiency...
January 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29297599/genetic-contribution-of-retinoid-related-genes-to-neural-tube-defects
#8
Huili Li, Jing Zhang, Shuyuan Chen, Fang Wang, Ting Zhang, Lee Niswander
Rare variants are considered underlying causes of complex diseases. The complex and severe group of disorders called neural tube defects (NTDs) results from failure of the neural tube to close during early embryogenesis. Neural tube closure requires the coordination of numerous signaling pathways, including the precise regulation of retinoic acid (RA) concentration which is controlled by enzymes involved in RA synthesis and degradation. Here we used a case-control mutation screen study to reveal rare variants in retinoid related genes in a Han Chinese NTD population by sequencing six genes in 355 NTD cases and 225 controls...
January 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29288557/alu-element-insertion-in-pklr-gene-as-a-novel-cause-of-pyruvate-kinase-deficiency-in-middle-eastern-patients
#9
Harry Lesmana, Lisa Dyer, Xia Li, James Denton, Jenna Griffiths, Satheesh Chonat, Katie G Seu, Matthew M Heeney, Kejian Zhang, Robert J Hopkin, Theodosia A Kalfa
Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass...
December 30, 2017: Human Mutation
https://www.readbyqxmd.com/read/29285825/targeted-copy-number-screening-highlights-an-intragenic-deletion-of-wdr63-as-the-likely-cause-of-human-occipital-encephalocele-and-abnormal-cns-development-in-zebrafish
#10
Wolfgang Hofmeister, Maria Pettersson, Deniz Kurtoglu, Miriam Armenio, Jesper Eisfeldt, Nikos Papadogiannakis, Peter Gustavsson, Anna Lindstrand
Congenital malformations affecting the neural tube can present as isolated malformations or occur in association with other developmental abnormalities and syndromes. Using high resolution copy number screening in 66 fetuses with neural tube defects we identified 6 fetuses with likely pathogenic mutations, three aneuploidies (one trisomy 13 and two trisomy 18) and three deletions previously reported in NTDs (one 22q11.2 deletion and two 1p36 deletions) corresponding to 9% of the cohort. In addition, we identified five rare deletions and two duplications of uncertain significance including a rare intragenic heterozygous in-frame WDR63 deletion in a fetus with occipital encephalocele...
December 28, 2017: Human Mutation
https://www.readbyqxmd.com/read/29282786/methods-and-tools-for-assessing-the-impact-of-genetic-variations-the-2017-annual-scientific-meeting-of-the-human-genome-variation-society
#11
William S Oetting, Christophe Béroud, Steven E Brenner, Marc S Greenblatt, Rachel Karchin, Sean D Mooney
  This article is protected by copyright. All rights reserved.
December 28, 2017: Human Mutation
https://www.readbyqxmd.com/read/29282796/disease-causing-mutations-in-the-promoter-and-enhancer-of-the-ornithine-transcarbamylase-gene
#12
Yoon J Jang, Abigail L LaBella, Timothy P Feeney, Nancy Braverman, Mendel Tuchman, Hiroki Morizono, Nicholas Ah Mew, Ljubica Caldovic
The ornithine transcarbamylase (OTC) gene is on the X chromosome and its product catalyzes the formation of citrulline from ornithine and carbamylphosphate in the urea cycle. About 10-15% of patients, clinically diagnosed with OTC deficiency (OTCD), lack identifiable mutations in the coding region or splice junctions of the OTC gene on routine molecular testing. We collected DNA from such patients via retrospective review and by prospective enrollment. In nine of 38 subjects (24%), we identified a sequence variant in the OTC regulatory regions...
December 27, 2017: Human Mutation
https://www.readbyqxmd.com/read/29282788/mpv17-related-mitochondrial-dna-maintenance-defect-new-cases-and-review-of-clinical-biochemical-and-molecular-aspects
#13
Ayman W El-Hattab, Julia Wang, Hongzheng Dai, Mohammed Almannai, Christian Staufner, Majid Alfadhel, Michael J Gambello, Pankaj Prasun, Saleem Raza, Hernando J Lyons, Manal Afqi, Mohammed A M Saleh, Eissa A Faqeih, Hamad I Alzaidan, Abduljabbar Alshenqiti, Leigh Anne Flore, Jozef Hertecant, Stephanie Sacharow, Deborah S Barbouth, Kei Murayama, Amit A Shah, Henry C Lin, Lee-Jun C Wong
Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants...
December 27, 2017: Human Mutation
https://www.readbyqxmd.com/read/29280214/thorough-in-silico-and-in-vitro-cdna-analysis-of-21-putative-brca1-and-brca2-splice-variants-and-a-complex-tandem-duplication-in-brca2-allowing-the-identification-of-activated-cryptic-splice-donor-sites-in-brca2-exon-11
#14
Annelot Baert, Eva Machackova, Ilse Coene, Carol Cremin, Kristin Turner, Cheryl Portigal-Todd, Marie Jill Asrat, Jennifer Nuk, Allison Mindlin, Young Sean, Andree MacMillan, Tom Van Maerken, Martin Trbusek, Wendy McKinnon, Marie E Wood, William D Foulkes, Marta Santamariña, Miguel de la Hoya, Lenka Foretova, Bruce Poppe, Anne Vral, Toon Rosseel, Kim De Leeneer, Ana Vega, Kathleen B M Claes
For 21 putative BRCA1 and BRCA2 splice site variants the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implement these novel tools in clinical settings...
December 27, 2017: Human Mutation
https://www.readbyqxmd.com/read/29271547/cis-variants-identified-in-f508del-complex-alleles-modulate-cftr-channel-rescue-by-small-molecules
#15
Nesrine Baatallah, Sara Bitam, Natacha Martin, Nathalie Servel, Bruno Costes, Chadia Mekki, Benoit Chevalier, Iwona Pranke, Juliette Simonin, Emmanuelle Girodon, Brice Hoffmann, Jean-Paul Mornon, Isabelle Callebaut, Isabelle Sermet-Gaudelus, Pascale Fanen, Aleksander Edelman, Alexandre Hinzpeter
Molecules correcting the trafficking (correctors) and gating defects (potentiators) of the cystic fibrosis causing mutation c.1521_1523delCTT (p.Phe508del) begin to be a useful treatment for CF patients bearing p.Phe508del. This mutation has been identified in different genetic contexts, alone or in combination with variants in cis. Until now, 21 exonic variants in cis of p.Phe508del have been identified, albeit at a low frequency. The aim of this study was to evaluate their impact on the efficacy of CFTR directed corrector/potentiator therapy (Orkambi)...
December 22, 2017: Human Mutation
https://www.readbyqxmd.com/read/29266534/myo5b-stx3-and-stxbp2-mutations-reveal-a-common-disease-mechanism-that-unifies-a-subset-of-congenital-diarrheal-disorders-a-mutation-update
#16
Herschel S Dhekne, Olena Pylypenko, Arend W Overeem, Rosaria J Ferreira, K Joeri van der Velde, Edmond H H M Rings, Carsten Posovszky, Morris A Swertz, Anne Houdusse, Sven C D van IJzendoorn
Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013 we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder...
December 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/29266598/nemaline-myopathy-and-distal-arthrogryposis-associated-with-an-autosomal-recessive%C3%A2-tnnt3%C3%A2-splice-variant
#17
Sarah A Sandaradura, Adam Bournazos, Amali Mallawaarachchi, Beryl B Cummings, Leigh B Waddell, Kristi J Jones, Christopher Troedson, Annapurna Sudarsanam, Benjamin M Nash, Gregory B Peters, Elizabeth M Algar, Daniel G MacArthur, Kathryn N North, Susan Brammah, Amanda Charlton, Nigel G Laing, Meredith J Wilson, Mark R Davis, Cooper Sandra T
A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibres with striking nemaline rods and hypertrophy of slow fibres that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin-Tfast and is associated with autosomal dominant distal arthrogryposis...
December 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/29266521/exonic-mutations-and-exon-skipping-lessons-learned-from-dfna5
#18
Kevin T Booth, Hela Azaiez, Kimia Kahrizi, Donghong Wang, Yuzhou Zhang, Kathy Frees, Carla Nishimura, Hossein Najmabadi, Richard J Smith
Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness-associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5-related deafness. In five families with postlingual progressive autosomal dominant non-syndromic hearing loss, we employed two next generation sequencing platforms - OtoSCOPE and whole exome sequencing - followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families...
December 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/29250858/structural-and-sequence-variants-in-patients-with-silver-russell-syndrome-or-similar-features-curation-of-a-disease-database
#19
Zeynep Tümer, Julia Angélica López-Hernández, Irène Netchine, Miriam Elbracht, Karen Grønskov, Lene Bjerring Gede, Jana Sachwitz, Johan T den Dunen, Thomas Eggermann
Silver-Russell syndrome (SRS) is a clinically and molecularly heterogeneous disorder involving prenatal and postnatal growth retardation, and the term SRS-like is broadly used to describe individuals with clinical features resembling SRS. The main molecular subgroups are loss of methylation of the distal imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 (50%) and maternal uniparental disomy of chromosome 7 (5-10%). Through a comprehensive literature search we identified 91 patients/families with various structural and small sequence variants, which were suggested as additional molecular defects leading to SRS/SRS-like phenotypes...
December 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/29243290/a-non-coding-variant-in-ganab-explains-isolated-polycystic-liver-disease-pcld-in-a-large-family
#20
Whitney Besse, Jungmin Choi, Dina Ahram, Shrikant Mane, Simone Sanna-Cherchi, Vicente Torres, Stefan Somlo
Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with 5 affected siblings for which no loss of function variants were identified by whole exome sequencing analysis. SNP genotyping and linkage analysis narrowed the candidate regions to ∼8% of the genome, which included two published PCLD genes in close proximity to each other, GANAB and LRP5...
December 15, 2017: Human Mutation
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