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Human Mutation

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https://www.readbyqxmd.com/read/28801929/validation-and-application-of-a-novel-integrated-genetic-screening-method-to-a-cohort-of-1-112-men-with-idiopathic-azoospermia-or-severe-oligozoospermia
#1
Manon S Oud, Liliana Ramos, Moira K O'Bryan, Robert I McLachlan, Özlem Okutman, Stephane Viville, Petra F de Vries, Dominique F C M Smeets, Dorien Lugtenberg, Jayne Y Hehir-Kwa, Christian Gilissen, Maartje van de Vorst, Lisenka E L M Vissers, Alexander Hoischen, Aukje M Meijerink, Kathrin Fleischer, Joris A Veltman, Michiel J Noordam
Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY) and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations (CNVs) affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes...
August 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28795510/cngb3-mutation-spectrum-including-copy-number-variations-in-485-achromatopsia-patients
#2
Anja Kathrin Mayer, Caroline Van Cauwenbergh, Christine Rother, Britta Baumann, Peggy Reuter, Elfride De Baere, Bernd Wissinger, Susanne Kohl
Achromatopsia is a rare autosomal recessive cone disorder characterized by color vision defects, photophobia, nystagmus and severely reduced visual acuity. The disease is caused by mutations in genes encoding crucial components of the cone phototransduction cascade (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) or in ATF6, involved in the unfolded protein response. CNGB3 encoding the beta subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors is the major achromatopsia gene. Here, we present a comprehensive spectrum of CNGB3 mutations and their prevalence in a cohort of 1,074 independent families clinically diagnosed with achromatopsia...
August 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28779497/pax7-mutation-in-a-syndrome-of-failure-to-thrive-hypotonia-and-global-neuro-developmental-delay
#3
Regina Proskorovski-Ohayon, Rotem Kadir, Analia Michalowski, Hagit Flusser, Yonatan Perez, Eli Hershkovitz, Sara Sivan, Ohad S Birk
PAX7 encodes a transcription factor essential in neural crest formation, myogenesis and pituitary lineage specification. Pax7 null mice fail to thrive and exhibit muscle weakness, dying within 3 weeks. We describe a human autosomal recessive syndrome, with failure to thrive, severe global developmental delay, microcephaly, axial hypotonia, pyramidal signs, dystonic postures, seizures, irritability and self-mutilation. Aside from low blood carnitine levels, biochemical and metabolic screen was normal, with growth hormone deficiency in one patient...
August 4, 2017: Human Mutation
https://www.readbyqxmd.com/read/28776325/identification-and-functional-characterization-of-two-missense-mutations-in-ndrg1-associated-with-charcot-marie-tooth-disease-type-4d-cmt4d
#4
Li-Xi Li, Gong-Lu Liu, Zhi-Jun Liu, Cong Lu, Zhi-Ying Wu
Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 - c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8 - have been described in CMT4D patients. Here, using targeted next-generation sequencing (NGS) examination, we identified for the first time two homozygous missense variants in NDRG1, c...
August 3, 2017: Human Mutation
https://www.readbyqxmd.com/read/28762608/truncating-mutation-in-csnk2b-and-myoclonic-epilepsy
#5
LETTER
Yuri Sakaguchi, Tomoko Uehara, Hisato Suzuki, Kenjiro Kosaki, Toshiki Takenouchi
No abstract text is available yet for this article.
August 1, 2017: Human Mutation
https://www.readbyqxmd.com/read/28762582/detection-of-homozygous-deletions-in-tumor-suppressor-genes-ranging-from-dozen-to-hundreds-nucleotides-in-cancer-models
#6
Lun-Ching Chang, Suleyman Vural, Dmitriy Sonkin
Tumor suppressor genes can be inactivated by several mechanisms and, in a majority of cases, both alleles need to be affected. One of the mechanisms of inactivation is due to deletions ranging from dozen to hundreds of nucleotides; such deletions are often missed by variant callers. HomDelDetect is a method to detect such homozygous deletions in cancer models, such as cancer cell lines and potentially patient tumor derived xenografts. This method can be applied to partial exome, whole exome, whole genome sequencing, and RNA-seq data...
August 1, 2017: Human Mutation
https://www.readbyqxmd.com/read/28762252/enzymatic-characterization-of-novel-arylsulfatase-a-variants-using-human-arylsulfatase-a-deficient-immortalized-mesenchymal-stromal-cells
#7
Judith Böhringer, René Santer, Neele Schumacher, Friederike Gieseke, Kerstin Cornils, Maria Pechan, Birgit Kustermann-Kuhn, Rupert Handgretinger, Ludger Schöls, Klaus Harzer, Ingeborg Krägeloh-Mann, Ingo Müller
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here we report the biochemical characterization of 7 novel pathogenic variants (c.98T > C, c.195delC, c...
July 31, 2017: Human Mutation
https://www.readbyqxmd.com/read/28752568/idua-mutational-profile-and-genotype-phenotype-relationships-in-uk-patients-with-mucopolysaccharidosis-i
#8
Arunabha Ghosh, Jean Mercer, Sabrina Mackinnon, Wyatt W Yue, Heather Church, Clare E Beesley, Alex Broomfield, Simon A Jones, Karen Tylee
Mucopolysaccharidosis Type I is a lysosomal storage disorder with varying degrees of phenotypic severity caused by mutations in IDUA. Over 200 disease-causing variants in IDUA have been reported. We describe the profile of disease-causing variants in 291 individuals with Mucopolysaccharidosis Type I for whom IDUA sequencing was performed, focussing on the UK subset of the cohort. A total of 63 variants were identified, of which 20 were novel, and the functional significance of the novel variants is explored...
July 28, 2017: Human Mutation
https://www.readbyqxmd.com/read/28748604/implementing-pharmacogenomics-in-modern-health-care-the-2017-scientific-meeting-of-the-human-genome-variation-society
#9
Pauline Lanting, William S Oetting
No abstract text is available yet for this article.
July 27, 2017: Human Mutation
https://www.readbyqxmd.com/read/28744936/molecular-combing-reveals-complex-4q35-rearrangements-in-facioscapulohumeral-dystrophy
#10
Karine Nguyen, Francesca Puppo, Stéphane Roche, Marie-Cécile Gaillard, Charlène Chaix, Arnaud Lagarde, Marjorie Pierret, Catherine Vovan, Sylviane Olschwang, Emmanuelle Salort-Campana, Shahram Attarian, Marc Bartoli, Rafaëlle Bernard, Frédérique Magdinier, Nicolas Levy
Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As molecular diagnosis relying on Southern blot (SB) might be challenging in some cases, molecular combing (MC) was recently developed as an additional technique for FSHD diagnosis and exploration of the genomic organization of the 4q35 and 10q26 regions. In complement to the usual SB, we applied MC in a large cohort of 586 individuals with clinical FSHD...
July 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28744922/ifn-%C3%AE-r1-defects-mutation-update-and-description-of-the-ifngr1-variation-database
#11
Esther van de Vosse, Jaap T van Dissel
IFN-γ signaling is essential for the innate immune defense against mycobacterial infections. IFN-γ signals through the IFN-γ receptor, which consists of a tetramer of two IFN-γR1 chains in complex with two IFN-γR2 chains, where IFN-γR1 is the ligand-binding chain of the interferon-γ receptor and IFN-γR2 is the signal-transducing chain of the IFN-γ receptor. Germline mutations in the gene IFNGR1 encoding the IFN-γR1 cause a primary immunodeficiency that mainly leads to mycobacterial infections. Here, we review the molecular basis of this immunodeficiency in the 130 individuals described to date, and report mutations in five new individuals, bringing the total number to 135 individuals from 98 kindreds...
July 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28741757/equivalent-missense-variant-in-the-foxp2-and-foxp1-transcription-factors-causes-distinct-neurodevelopmental-disorders
#12
Elliot Sollis, Pelagia Deriziotis, Hirotomo Saitsu, Noriko Miyake, Naomichi Matsumoto, Mariëtte J V Hoffer, Claudia A L Ruivenkamp, Mariëlle Alders, Nobuhiko Okamoto, Emilia K Bijlsma, Astrid S Plomp, Simon E Fisher
The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability, and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients...
July 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28730625/fgf9-mutation-causes-craniosynostosis-along-with-multiple-synostoses
#13
Maria Rodriguez-Zabala, Miriam Aza-Carmona, Carlos I Rivera-Pedroza, Alberta Belinchón, Isabel Guerrero-Zapata, Jimena Barraza-García, Elena Vallespin, Min Lu, Angela Del Pozo, Marc J Glucksman, Fernando Santos-Simarro, Karen E Heath
Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF-mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next-generation sequencing, we identified a novel missense mutation in FGF9. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding...
July 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/28726266/survival-among-children-with-lethal-congenital-contracture-syndrome-11-caused-by-novel-mutations-in-the-gliomedin-gene-gldn
#14
Jennifer A Wambach, Georg M Stettner, Tobias B Haack, Karin Writzl, Andreja Škofljanec, Aleš Maver, Francina Munell, Stephan Ossowski, Mattia Bosio, Daniel J Wegner, Marwan Shinawi, Dustin Baldridge, Bader Alhaddad, Tim M Strom, Dorothy K Grange, Ekkehard Wilichowski, Robin Troxell, James Collins, Barbara B Warner, Robert E Schmidt, Alan Pestronk, F Sessions Cole, Robert Steinfeld
Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report 6 infants and children from 4 unrelated families with biallelic GLDN mutations, 4 of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support...
July 20, 2017: Human Mutation
https://www.readbyqxmd.com/read/28722338/hdr-del-a-tool-based-on-hamming-distance-for-prioritizing-pathogenic-chromosomal-deletions-in-exome-sequencing
#15
Atsuko Imai, Masakazu Kohda, Kaori Kobayashi, Tomoko Hirata, Yasushi Sakata, Kei Murayama, Akira Ohtake, Yasushi Okazaki, Akihiro Nakaya, Jurg Ott
High-density oligonucleotide arrays have been widely used to detect pathogenic chromosomal deletions. In addition to high-density oligonucleotide arrays, programs using whole exome sequencing have become available for estimating copy number variations using depth of coverage. Here we propose a new statistical method, HDR-del, to prioritize pathogenic chromosomal deletions based on Hamming distance in exome sequencing. In vcf (Variant Call Format) files generated from exome sequencing, hemizygous chromosomal deletion regions lack heterozygous variants and lead to apparent long runs of homozygosity (ROH)...
July 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/28722276/identification-and-functional-analysis-of-an-adamtsl1-variant-associated-with-a-complex-phenotype-including-congenital-glaucoma-craniofacial-and-other-systemic-features-in-a-three-generation-human-pedigree
#16
Kathryn Hendee, Lauren Weiping Wang, Linda M Reis, Gregory M Rice, Suneel S Apte, Elena V Semina
Developmental glaucoma can occur as an isolated or syndromic condition and is genetically heterogeneous. We describe a three-generation family affected with developmental glaucoma, myopia, and/or retinal defects associated with variable craniofacial/dental, auditory, brain, renal, and limb anomalies. Whole exome sequencing identified a heterozygous c.124T> C, p.(Trp42Arg) allele in ADAMTSL1; co-segregation analysis confirmed the presence of this allele in four affected family members. The mutation affects a highly conserved residue and is strongly predicted to have a deleterious effect on protein function...
July 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/28714244/the-role-of-de-novo-mutations-in-the-development-of-amyotrophic-lateral-sclerosis
#17
Perry T C van Doormaal, Nicola Ticozzi, Jochen H Weishaupt, Kevin Kenna, Frank P Diekstra, Federico Verde, Peter M Andersen, Annelot M Dekker, Cinzia Tiloca, Nicolai Marroquin, Daniel J Overste, Viviana Pensato, Peter Nürnberg, Sara L Pulit, Raymond D Schellevis, Daniela Calini, Janine Altmüller, Laurent C Francioli, Bernard Muller, Barbara Castellotti, Susanne Motameny, Antonia Ratti, Joachim Wolf, Cinzia Gellera, Albert C Ludolph, Leonard H van den Berg, Christian Kubisch, John E Landers, Jan H Veldink, Vincenzo Silani, Alexander E Volk
The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total)...
July 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/28714225/leveraging-splice-affecting-variant-predictors-and-a-minigene-validation-system-to-identify-mendelian-disease-causing-variants-amongst-exon-captured-variants-of-uncertain-significance
#18
Zachry T Soens, Justin Branch, Shijing Wu, Zhisheng Yuan, Yumei Li, Hui Li, Keqing Wang, Mingchu Xu, Lavan Rajan, Fabiana L Motta, Renata T Simões, Irma Lopez-Solache, Radwan Ajlan, David G Birch, Peiquan Zhao, Fernanda B Porto, Juliana Sallum, Robert K Koenekoop, Ruifang Sui, Rui Chen
The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS's) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation...
July 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/28714182/rare-coding-variants-in-mapk7-predispose-to-adolescent-idiopathic-scoliosis
#19
Wenjie Gao, Chong Chen, Taifeng Zhou, Shulan Yang, Bo Gao, Hang Zhou, Chengjie Lian, Zizhao Wu, Xianjian Qiu, Xiaoming Yang, Esam Alattar, Wentao Liu, Deying Su, Silong Sun, Yulan Chen, Kenneth M C Cheung, Youqiang Song, Keith K D Luk, Danny Chan, Pak Chung Sham, Chao Xing, Chiea Chuen Khor, Gabriel Liu, Junlin Yang, Yubin Deng, Dingjun Hao, Dongsheng Huang, Quan-Zhen Li, Caixia Xu, Peiqiang Su
Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2-3% of school age children, yet the causes underlying AIS are not well understood. Here, we firstly conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal dominant (AD) AIS, then performed targeted sequencing in a discovery cohort comprising 20 AD-AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c...
July 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/28703315/using-whole-exome-sequencing-to-investigate-the-genetic-bases-of-lysosomal-storage-diseases-of-unknown-etiology
#20
Nan Wang, Yeting Zhang, Erika Gedvilaite, Jui Wan Loh, Timothy Lin, Xiuping Liu, Chang-Gong Liu, Dibyendu Kumar, Robert Donnelly, Kimiyo Raymond, Edward H Schuchman, David E Sleat, Peter Lobel, Jinchuan Xing
Lysosomes are membrane-bound, acidic eukaryotic cellular organelles that play important roles in the degradation of macromolecules. Mutations that cause the loss of lysosomal protein function can lead to a group of disorders categorized as the lysosomal storage diseases (LSDs). Suspicion of LSD is frequently based on clinical and pathologic findings, but in some cases, the underlying genetic and biochemical defects remain unknown. Here, we performed whole exome sequencing (WES) on 14 suspected LSD cases to evaluate the feasibility of using WES for identifying causal mutations...
July 12, 2017: Human Mutation
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