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https://www.readbyqxmd.com/read/28549094/a-novel-dominant-mutation-in-sag-the-arrestin-1-gene-is-a-common-cause-of-retinitis-pigmentosa-in-hispanic-families-in-the-southwestern-united-states
#1
Lori S Sullivan, Sara J Bowne, Daniel C Koboldt, Elizabeth L Cadena, John R Heckenlively, Kari E Branham, Dianna H Wheaton, Kaylie D Jones, Richard S Ruiz, Mark E Pennesi, Paul Yang, David Davis-Boozer, Hope Northrup, Vsevold V Gurevich, Rui Chen, Mingchu Xu, Yumei Li, David G Birch, Stephen P Daiger
Purpose: To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG. Methods: Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28528644/bypassing-negative-epistasis-on-yield-in-tomato-imposed-by-a-domestication-gene
#2
Sebastian Soyk, Zachary H Lemmon, Matan Oved, Josef Fisher, Katie L Liberatore, Soon Ju Park, Anna Goren, Ke Jiang, Alexis Ramos, Esther van der Knaap, Joyce Van Eck, Dani Zamir, Yuval Eshed, Zachary B Lippman
Selection for inflorescence architecture with improved flower production and yield is common to many domesticated crops. However, tomato inflorescences resemble wild ancestors, and breeders avoided excessive branching because of low fertility. We found branched variants carry mutations in two related transcription factors that were selected independently. One founder mutation enlarged the leaf-like organs on fruits and was selected as fruit size increased during domestication. The other mutation eliminated the flower abscission zone, providing "jointless" fruit stems that reduced fruit dropping and facilitated mechanical harvesting...
May 15, 2017: Cell
https://www.readbyqxmd.com/read/28528518/a-multi-gene-panel-study-in-hereditary-breast-and-ovarian-cancer-in-colombia
#3
A M Cock-Rada, C A Ossa, H I Garcia, L R Gomez
Germline mutations in BRCA1 and BRCA2 account for approximately 50% of inherited breast and ovarian cancers. Three founder mutations in BRCA1/2 have been reported in Colombia, but the pattern of mutations in other cancer susceptibility genes is unknown. This study describes the frequency and type of germline mutations in hereditary breast and/or ovarian cancer genes in a referral cancer center in Colombia. Eighty-five women referred to the oncogenetics unit of the Instituto de Cancerologia Las Americas in Medellin (Colombia), meeting testing criteria for hereditary breast and ovarian cancer syndrome (NCCN 2015), who had germline testing with a commercial 25-gene hereditary cancer panel, were included in the analysis...
May 20, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28526081/comprehensive-detection-of-germline-variants-by-msk-impact-a-clinical-diagnostic-platform-for-solid-tumor-molecular-oncology-and-concurrent-cancer-predisposition-testing
#4
Donavan T Cheng, Meera Prasad, Yvonne Chekaluk, Ryma Benayed, Justyna Sadowska, Ahmet Zehir, Aijazuddin Syed, Yan Elsa Wang, Joshua Somar, Yirong Li, Zarina Yelskaya, Donna Wong, Mark E Robson, Kenneth Offit, Michael F Berger, Khedoudja Nafa, Marc Ladanyi, Liying Zhang
BACKGROUND: The growing number of Next Generation Sequencing (NGS) tests is transforming the routine clinical diagnosis of hereditary cancers. Identifying whether a cancer is the result of an underlying disease-causing mutation in a cancer predisposition gene is not only diagnostic for a cancer predisposition syndrome, but also has significant clinical implications in the clinical management of patients and their families. METHODS: Here, we evaluated the performance of MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) in detecting genetic alterations in 76 genes implicated in cancer predisposition syndromes...
May 19, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/28526070/the-golden-retriever-model-of-duchenne-muscular-dystrophy
#5
REVIEW
Joe N Kornegay
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development...
May 19, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28525759/modeling-rett-syndrome-using-talen-edited-mecp2-mutant-cynomolgus-monkeys
#6
Yongchang Chen, Juehua Yu, Yuyu Niu, Dongdong Qin, Hailiang Liu, Gang Li, Yingzhou Hu, Jiaojian Wang, Yi Lu, Yu Kang, Yong Jiang, Kunhua Wu, Siguang Li, Jingkuan Wei, Jing He, Junbang Wang, Xiaojing Liu, Yuping Luo, Chenyang Si, Raoxian Bai, Kunshan Zhang, Jie Liu, Shaoyong Huang, Zhenzhen Chen, Shuang Wang, Xiaoying Chen, Xinhua Bao, Qingping Zhang, Fuxing Li, Rui Geng, Aibin Liang, Dinggang Shen, Tianzi Jiang, Xintian Hu, Yuanye Ma, Weizhi Ji, Yi Eve Sun
Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28508084/clinicopathologic-and-molecular-spectrum-of-rnaseh1-related-mitochondrial-disease
#7
Enrico Bugiardini, Olivia V Poole, Andreea Manole, Alan M Pittman, Alejandro Horga, Iain Hargreaves, Cathy E Woodward, Mary G Sweeney, Janice L Holton, Jan-Willem Taanman, Gordon T Plant, Joanna Poulton, Massimo Zeviani, Daniele Ghezzi, John Taylor, Conrad Smith, Carl Fratter, Meena A Kanikannan, Arumugam Paramasivam, Kumarasamy Thangaraj, Antonella Spinazzola, Ian J Holt, Henry Houlden, Michael G Hanna, Robert D S Pitceathly
OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. METHODS: RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA...
June 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28503760/the-penetrance-of-paraganglioma-and-pheochromocytoma-in-sdhb-germline-mutation-carriers
#8
Johannes A Rijken, Nicolasine D Niemeijer, Marianne A Jonker, Karin Eijkelenkamp, Jeroen C Jansen, Anouk van Berkel, Henri J L M Timmers, Henricus P M Kunst, Peter H L T Bisschop, Michiel N Kerstens, Koen M A Dreijerink, Marieke F van Dooren, Anouk N A van der Horst-Schrivers, Frederik J Hes, C René Leemans, Eleonora P M Corssmit, Erik F Hensen
Germline mutations in SDHB predispose to hereditary paraganglioma syndrome type 4. The risk of developing paraganglioma (PGL) or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure...
May 14, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28503715/deficiency-of-interleukin-1-receptor-antagonist-dira-report-of-the-first-indian-patient-and-a-novel-deletion-affecting-il1rn
#9
Leonardo O Mendonca, Louise Malle, Frank X Donovan, Settara C Chandrasekharappa, Gina A Montealegre Sanchez, Megha Garg, Ulf Tedgard, Mariana Castells, Shiv S Saini, Sourabh Dutta, Raphaela Goldbach-Mansky, Deepti Suri, Adriana A Jesus
PURPOSE: Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized...
May 15, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28492130/osteogenesis-imperfecta-type-3-in-south-africa-causative-mutations-in-fkbp10
#10
Alvera Vorster, Peter Beighton, Manogari Chetty, Yasmeen Ganie, Bertram Henderson, Engela Honey, Piet Maré, David Thompson, Karen Fieggen, Denis Viljoen, Rajkumar Ramesar
BACKGROUND: A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment. OBJECTIVE: To delineate the molecular basis for the condition. METHODS: Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population...
April 25, 2017: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
https://www.readbyqxmd.com/read/28490599/the-phenotype-of-sdhb-germline-mutation-carriers-a-nationwide-study
#11
Nicolasine D Niemeijer, Johannes A Rijken, Karin Eijkelenkamp, A N A van der Horst-Schrivers, Michiel N Kerstens, Carli M Tops, Anouk van Berkel, Henri J Timmers, Henricus P M Kunst, C Rene Leemans, Peter H Bisschop, Koen Ma Dreijerink, Marieke van Dooren, Jean-Pierre Bayley, Alberto M Pereira, Jeroen Jansen, Frederik J Hes, Erik Hensen, E P Corssmit
Objective Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas, and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations. Design Retrospective descriptive study...
May 10, 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28488383/pax6-allelic-heterogeneity-in-mexican-congenital-aniridia-patients-expanding-the-mutational-spectrum-with-7-novel-pathogenic-variants
#12
Sofía Pérez-Solórzano, Oscar F Chacón-Camacho, Mirena C Astiazarán, Gerardo Ledesma-Gil, Juan Carlos Zenteno
IMPORTANCE: To describe the clinical characteristics and mutational analysis of Mexican patients with aniridia and PAX6 mutations. BACKGROUND: Aniridia is a panocular hereditary eye disease caused by mutations in the PAX6 transcription factor. Mutation detection rate is highly variable ranging from 30 to 90% in different populations. Very few studies have been published about the PAX6 mutational analysis in aniridia patients from Mexico. In order to establish a more representative PAX6 mutational frequency in the country, a cohort of 22 Mexican unrelated aniridia probands were analyzed in this study...
May 9, 2017: Clinical & Experimental Ophthalmology
https://www.readbyqxmd.com/read/28488341/next-generation-sequencing-targeted-disease-panel-in-rod-cone-retinal-dystrophies-in-m%C3%A4-ori-and-polynesian-reveals-novel-changes-and-a-common-founder-mutation
#13
Andrea L Vincent, Nandoun Abeysekera, Katherine A van Bysterveldt, Verity F Oliver, Jamie M Ellingford, Stephanie Barton, Graeme Cm Black
IMPORTANCE: This study identifies unique genetic variation observed in a cohort of Māori and Polynesian patients with rod-cone retinal dystrophies using a targeted Next Generation Sequencing (NGS) retinal disease gene panel BACKGROUND: With over 250 retinal disease genes identified, genetic diagnosis is still only possible in 60-70% of individuals, and even less within unique ethnic groups. DESIGN: Prospective genetic testing in patients with rod-cone retinal dystrophies identified from the New Zealand Inherited Retinal Disease (IRD) Database, PARTICIPANTS: Sixteen Patients of Māori and Polynesian ancestry...
May 9, 2017: Clinical & Experimental Ophthalmology
https://www.readbyqxmd.com/read/28486781/genomic-analysis-of-inherited-breast-cancer-among-palestinian-women-genetic-heterogeneity-and-a-founder-mutation-in-tp53
#14
Suhair Lolas Hamameh, Paul Renbaum, Lara Kamal, Dima Dweik, Mohammad Salahat, Tamara Jaraysa, Amal Abu Rayyan, Silvia Casadei, Jessica B Mandell, Suleyman Gulsuner, Ming K Lee, Tom Walsh, Mary-Claire King, Ephrat Levy-Lahad, Moein Kanaan
Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital-based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother or aunt ("discovery series"); and 422 women diagnosed after age 40 and with negative family history ("older-onset sporadic patient series")...
May 9, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28482133/estimating-the-probability-of-clonal-relatedness-of-pairs-of-tumors-in-cancer-patients
#15
Audrey Mauguen, Venkatraman E Seshan, Irina Ostrovnaya, Colin B Begg
Next generation sequencing panels are being used increasingly in cancer research to study tumor evolution. A specific statistical challenge is to compare the mutational profiles in different tumors from a patient to determine the strength of evidence that the tumors are clonally related, that is, derived from a single, founder clonal cell. The presence of identical mutations in each tumor provides evidence of clonal relatedness, although the strength of evidence from a match is related to how commonly the mutation is seen in the tumor type under investigation...
May 8, 2017: Biometrics
https://www.readbyqxmd.com/read/28472934/novel-npc1-mutations-with-different-segregation-in-two-related-greek-patients-with-niemann-pick-type-c-disease-molecular-study-in-the-extended-pedigree-and-clinical-correlations
#16
Evangelia Bountouvi, Anna Papadopoulou, Marie T Vanier, Georgia Nyktari, Spyridon Kanellakis, Helen Michelakakis, Argyrios Dinopoulos
BACKGROUND: Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse. METHODS: The study population consisted of two Greek NPC patients and their extended pedigree. Patients' clinical, biochemical, molecular profiles and the possible correlations are presented...
May 4, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28469144/a-deep-intronic-clrn1-ush3a-founder-mutation-generates-an-aberrant-exon-and-underlies-severe-usher-syndrome-on-the-arabian-peninsula
#17
Arif O Khan, Elvir Becirovic, Christian Betz, Christine Neuhaus, Janine Altmüller, Lisa Maria Riedmayr, Susanne Motameny, Gudrun Nürnberg, Peter Nürnberg, Hanno J Bolz
Deafblindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes - to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28469084/broadly-neutralizing-antibodies-with-few-somatic-mutations-and-hepatitis-c-virus-clearance
#18
Justin R Bailey, Andrew I Flyak, Valerie J Cohen, Hui Li, Lisa N Wasilewski, Anna E Snider, Shuyi Wang, Gerald H Learn, Nurgun Kose, Leah Loerinc, Rebecca Lampley, Andrea L Cox, Jennifer M Pfaff, Benjamin J Doranz, George M Shaw, Stuart C Ray, James E Crowe
Here, we report the isolation of broadly neutralizing mAbs (bNAbs) from persons with broadly neutralizing serum who spontaneously cleared hepatitis C virus (HCV) infection. We found that bNAbs from two donors bound the same epitope and were encoded by the same germline heavy chain variable gene segment. Remarkably, these bNAbs were encoded by antibody variable genes with sparse somatic mutations. For one of the most potent bNAbs, these somatic mutations were critical for antibody neutralizing breadth and for binding to autologous envelope variants circulating late in infection...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469040/mutations-in-the-vesicular-trafficking-protein-annexin-a11-are-associated-with-amyotrophic-lateral-sclerosis
#19
Bradley N Smith, Simon D Topp, Claudia Fallini, Hideki Shibata, Han-Jou Chen, Claire Troakes, Andrew King, Nicola Ticozzi, Kevin P Kenna, Athina Soragia-Gkazi, Jack W Miller, Akane Sato, Diana Marques Dias, Maryangel Jeon, Caroline Vance, Chun Hao Wong, Martina de Majo, Wejdan Kattuah, Jacqueline C Mitchell, Emma L Scotter, Nicholas W Parkin, Peter C Sapp, Matthew Nolan, Peter J Nestor, Michael Simpson, Michael Weale, Monkel Lek, Frank Baas, J M Vianney de Jong, Anneloor L M A Ten Asbroek, Alberto Garcia Redondo, Jesús Esteban-Pérez, Cinzia Tiloca, Federico Verde, Stefano Duga, Nigel Leigh, Hardev Pall, Karen E Morrison, Ammar Al-Chalabi, Pamela J Shaw, Janine Kirby, Martin R Turner, Kevin Talbot, Orla Hardiman, Jonathan D Glass, Jacqueline De Belleroche, Masatoshi Maki, Stephen E Moss, Christopher Miller, Cinzia Gellera, Antonia Ratti, Safa Al-Sarraj, Robert H Brown, Vincenzo Silani, John E Landers, Christopher E Shaw
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p...
May 3, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28467518/mutation-spectrum-of-star-and-a-founder-effect-of-the-p-q258-in-korean-patients-with-congenital-lipoid-adrenal-hyperplasia
#20
Eungu Kang, Yoon-Myung Kim, Gu-Hwan Kim, Beom Hee Lee, Han-Wook Yoo, Jin-Ho Choi
Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia, caused by defects in the steroidogenic acute regulatory protein (STAR). The STAR p.Q258* mutation is the most common mutation in China, Japan, and Korea, suggesting a founder effect. This study aimed to investigate the phenotypic and mutation spectrum of STAR defects and identify a founder effect of the p.Q258* mutation in Korean patients with CLAH. For 45 patients from 42 independent pedigrees, haplotype analysis was performed in 10 unrelated trio families, including patients with the p...
May 2, 2017: Molecular Medicine
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