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Cold Spring Harbor Molecular Case Studies

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https://www.readbyqxmd.com/read/28729373/the-importance-of-managing-the-patient-and-not-the-gene-expanded-phenotype-of-gle1-associated-arthrogryposis
#1
Queenie K-G Tan, Allyn McConkie-Rosell, Jane Juusola, Kathryn E Gustafson, Carolyn E Pizoli, Anne F Buckley, Yong-Hui Jiang
GLE1 encodes a protein important for mRNA export and appears to play roles in translation initiation and termination as well. Pathogenic variants in GLE1 mutations have been associated with lethal contracture syndrome (LCCS1) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD); phenotypes reported in individuals include fetal akinesia and a severe form of motor neuron disease, typically presenting with prenatal symptoms and perinatal lethality. In this paper, we identified bi-allelic missense mutations in GLE1 by trio whole exome sequencing (WES) in an individual affected with congenital motor weakness and contractures as well as feeding and respiratory difficulties...
July 20, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28701297/genomic-analysis-of-an-infant-with-intractable-diarrhea-and-dilated-cardiomyopathy
#2
Dale L Bodian, Thierry Vilboux, Suchitra K Hourigan, Callie L Jenevein, Haresh Mani, Kathleen C Kent, Alina Khromykh, Benjamin D Solomon, Natalie S Hauser
We describe a case of an infant presenting with intractable diarrhea who subsequently developed dilated cardiomyopathy, for whom a diagnosis was not initially achieved despite extensive clinical testing, including panel-based genetic testing. Research-based whole genome sequences of the proband and both parents were analyzed by the SAVANNA pipeline, a variant prioritization strategy integrating features of variants, genes, and phenotypes, which was implemented using publicly available tools. Although the intestinal morphological abnormalities characteristic of congenital tufting enteropathy (CTE) were not observed in the initial clinical gastrointestinal tract biopsies of the proband, an intronic variant, EPCAM c...
July 12, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28696212/compound-heterozygous-slc19a3-mutations-further-refine-the-critical-promoter-region-for-biotin-thiamine-responsive-basal-ganglia-disease
#3
Whitney Whitford, Isobel Hawkins, Emma Glamuzina, Francessa Wilson, Andrew Marshall, Fern Ashton, Donald R Love, Juliet Taylor, Rosamund Hill, Klaus Lehnert, Russell G Snell, Jessie C Jacobsen
Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early-childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant life-long improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole genome sequencing...
July 10, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28667000/whole-exome-sequencing-identifies-an-%C3%AE-globin-cluster-triplication-resulting-in-increased-clinical-severity-of-%C3%AE-thalassemia
#4
Orna Steinberg-Shemer, Jacob C Ulirsch, Sharon Noy-Lotan, Tanya Krasnov, Dina Attias, Orly Dgany, Ruth Laor, Vijay G Sankaran, Hannah Tamary
Whole exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-year old man with a life-long moderate to severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor...
June 30, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28655807/germ-line-brca2-mutations-detected-in-pediatric-sequencing-studies-impact-parents-evaluation-and-care
#5
Michael F Walsh, Jennifer Kennedy, Megan Harlan, Alex Kentsis, Neerav Shukla, Stephen Roberts, Andrew L Kung, Mark Robson, Brian H Kushner, Paul Meyers, Kenneth Offit
There has been no indication to test for BRCA1/2 in children (with the rare exception of Fanconi Anemia) as screening begins in adult years and the potential to induce anxiety related to adult onset cancers. However in the setting of pediatric cancer, with increasing utility and frequency of companion tumor-normal sequencing without regard for phenotype and with BRCA1/2 included in tumor profiling panels, germline mutations in BRCA1/2 and other DNA damage repair genes have been found. When mutations in these genes are revealed, there are implications for immediate family members...
June 27, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28652255/identification-of-a-novel-mutation-in-aptx-gene-associated-with-ataxia-oculomotor-apraxia
#6
Jingga Inlora, M Reza Sailani, Hamidreza Khodadadi, Ahmad Teymurinezhad, Shinichi Takahashi, Jonathan A Bernstein, Masoud Garshasbi, Michael P Snyder
Hereditary ataxias are clinically and genetically heterogeneous family of disorders defined by the inability to control gait and muscle coordination. Given the non-specific symptoms of many hereditary ataxias, precise diagnosis relies on molecular genetic testing. To this end, we conducted whole exome sequencing (WES) on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia. WES in five affected and six unaffected individuals resulted in the identification of a homozygous novel stop-gain mutation in APTX gene (c...
June 26, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28630369/alpk3-gene-mutation-in-a-patient-with-congenital-cardiomyopathy-and-dysmorphic-features
#7
Ahmet Okay Cağlayan, Rabia Gonul Sezer, Hande Kaymakcalan, Ege Ulgen, Taner Yavuz, Jacob F Baranoski, Abdulkadir Bozaykut, Akdes Serin Harmanci, Yalim Yalcin, Mark W Youngblood, Katsuhito Yasuno, Kaya Bilguvar, Murat Gunel
Primary cardiomyopathy is one of the most common inherited cardiac diseases and harbors significant phenotypic and genetic heterogeneity. Because of this, genetic testing has become standard in treatment of this disease group. Indeed, in recent years, next-generation DNA sequencing has found broad applications in medicine, both as a routine diagnostic tool for genetic disorders and also as a high-throughput discovery tool for identifying novel disease causing genes. We describe a male infant with primary dilated cardiomyopathy that was diagnosed using intrauterine echocardiography, and found to progress to hypertrophic cardiomyopathy after birth...
June 19, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28619747/successful-immune-checkpoint-blockade-in-a-patient-with-advanced-stage-microsatellite-unstable-biliary-tract-cancer
#8
Elena Czink, Matthias Kloor, Benjamin Goeppert, Stefan Froehling, Sebastian Uhrig, Tim F Weber, Joern Meinel, Christian Sutter, Karl Heinz Weiss, Peter Schirmacher, Magnus von Knebel Doeberitz, Dirk Jaeger, Christoph Springfeld
Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy...
June 15, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28550066/rapid-whole-genome-sequencing-identifies-a-novel-homozygous-npc1-variant-associated-with-niemann-pick-type-c1-disease-in-a-7-week-old-male-with-cholestasis
#9
Amber Hildreth, Kristen Wigby, Shimul Chowdhury, Shareef Nahas, Jaime Barea, Paulina Ordonez, Serge Batalov, David M Dimmock, Rcigm Investigators, Stephen F Kingsmore
Niemann-Pick Type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. While characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction due to intrahepatocyte lipid accumulation. We report a 7 week old who was admitted with neonatal cholestasis, who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole genome sequencing (WGS)...
May 26, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28550065/exceptional-durable-response-to-everolimus-in-a-patient-with-biphenotypic-breast-cancer-harboring-an-stk11-variant
#10
Christine A Parachoniak, Andrew Rankin, Bernadette Gaffney, Ryan Hartmaier, Dan Spritz, Rachel L Erlich, Vincent A Miller, Deborah Morosini, Phil Stephens, Jeffrey S Ross, John Keech, Juliann Chmielecki
Metastatic triple negative breast cancer comprises 12-17% of breast cancers and carries a poor prognosis relative to other breast cancer subtypes. Treatment options in this disease are largely limited to systemic chemotherapy. A majority of clinical studies assessing efficacy of targeted therapeutics (e.g. the mTOR inhibitor everolimus) in advanced breast cancer patients have not utilized predictive genomic biomarker-based selection and have reported only modest improvement in clinical outcome relative to standard of care...
May 26, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28514723/genomic-profiling-of-pelvic-genital-type-leiomyosarcoma-in-a-woman-with-a-germline-chek2-c-1100delc-mutation-and-a-concomitant-diagnosis-of-metastatic-invasive-ductal-breast-carcinoma
#11
My Linh Thibodeau, Caralyn Reisle, Eric Zhao, Lee Ann Martin, Yazeed Alwelaie, Karen L Mungall, Carolyn Ch'ng, Ruth Thomas, Tony Ng, Stephen Yip, Howard Lim, Sophie Sun, Sean S Young, Aly Karsan, Yongjun Zhao, Andrew J Mungall, Richard A Moore, Daniel Renouf, Karen Gelmon, Yussanne P Ma, Malcolm Hayes, Janessa Laskin, Marco A Marra, Kasmintan A Schrader, Steven J M Jones
INTRODUCTION: We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumour suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximate 2-fold increase in breast cancer risk...
May 16, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679694/understanding-physical-activity-in-cancer-patients-and-survivors-new-methodology-new-challenges-and-new-opportunities
#12
REVIEW
Jennifer A Schrack, Gillian Gresham, Amal A Wanigatunga
Since the early 1990s, accumulating evidence has suggested that regular, sustained participation in physical activity may help prevent the onset and development of certain types of cancer. Given the worldwide incidence and prevalence of cancer, there is increasing interest in physical activity as a nonpharmacological intervention and prevention method. Moreover, the effectiveness of new and improved cancer therapies has also increased interest in the potential health benefits of physical activity during and after treatment...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679693/functional-validation-reveals-the-novel-missense-v419l-variant-in-tgfbr2-associated-with-loeys-dietz-syndrome-lds-impairs-canonical-tgf-%C3%AE-signaling
#13
Margot A Cousin, Michael T Zimmermann, Angela J Mathison, Patrick R Blackburn, Nicole J Boczek, Gavin R Oliver, Gwen A Lomberk, Raul A Urrutia, David R Deyle, Eric W Klee
TGF-β-related heritable connective tissue disorders are characterized by a similar pattern of cardiovascular defects, including aortic root dilatation, mitral valve prolapse, vascular aneurysms, and vascular dissections and exhibit incomplete penetrance and variable expressivity. Because of the phenotypic overlap of these disorders, panel-based genetic testing is frequently used to confirm the clinical findings. Unfortunately in many cases, variants of uncertain significance (VUSs) obscure the genetic diagnosis until more information becomes available...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679692/an-unusual-genomic-variant-of-pancreatic-ductal-adenocarcinoma-with-an-indolent-clinical-course
#14
Zachary A Kohutek, Lauren M Rosati, Junguei Hong, Justin Poling, Marc A Attiyeh, Alvin Makohon-Moore, Joseph M Herman, Christine A Iacobuzio-Donahue
We describe an 85-yr-old male of Ashkenazi Jewish descent with biopsy-proven locally advanced pancreatic ductal adenocarcinoma (PDA). The patient underwent a modified course of gemcitabine and stereotactic body radiation therapy and survived for 42 mo with a stable pancreatic head mass and no evidence of metastatic disease before death due to complications from a stroke. Whole-exome sequencing of his tumor revealed a simple genome landscape with no evidence of mutations, copy-number changes, or structural alterations in genes most commonly associated with PDA (i...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679691/metastatic-triple-negative-breast-cancer-patient-with-tp53-tumor-mutation-experienced-11-months-progression-free-survival-on-bortezomib-monotherapy-without-adverse-events-after-ending-standard-treatments-with-grade-3-adverse-events
#15
Tobias Meißner, Adam Mark, Casey Williams, Wolfgang E Berdel, Stephanie Wiebe, Andrea Kerkhoff, Eva Wardelmann, Timo Gaiser, Carsten Müller-Tidow, Philip Rosenstiel, Norbert Arnold, Brian Leyland-Jones, Andre Franke, Martin Stanulla, Michael Forster
A triple-negative breast cancer patient had no hereditary BRCA1, BRCA2, or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679690/spg20-mutation-in-three-siblings-with-familial-hereditary-spastic-paraplegia
#16
Leila Dardour, Filip Roelens, Valerie Race, Erika Souche, Maureen Holvoet, Koen Devriendt
Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679689/two-different-mutually-exclusively-distributed-tp53-mutations-in-ovarian-and-peritoneal-tumor-tissues-of-a-serous-ovarian-cancer-patient-indicative-for-tumor-origin
#17
Nyamdelger Sukhbaatar, Anna Bachmayr-Heyda, Katharina Auer, Stefanie Aust, Simon Deycmar, Reinhard Horvat, Dietmar Pils
High-grade serous ovarian cancer (HGSOC) is characterized by a TP53 mutation rate of up to 96.7% and associated with a more aggressive tumor biology. The origin of HGSOC is thought to arise either from fallopian tube secretory cells or the ovarian surface epithelium/inclusion cysts, the former with more evidence. Peritoneal tumor spread is heterogeneous, either excessive in the peritoneum (with miliary appearance) or more confined to the ovaries with only few (bigger and exophytically growing) peritoneal implants...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28679688/compound-heterozygous-alterations-in-intraflagellar-transport-protein-cluap1-in-a-child-with-a-novel-joubert-and-oral-facial-digital-overlap-syndrome
#18
Jennifer J Johnston, Chanjae Lee, Ingrid M Wentzensen, Melissa A Parisi, Molly M Crenshaw, Julie C Sapp, Jeffrey M Gross, John B Wallingford, Leslie G Biesecker
Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28487886/new-tools-and-approaches-to-newborn-screening-ready-to-open-pandora-s-box
#19
Can Ficicioglu
The landscape of newborn screening (NBS) is changing as new tools are developed. We must acknowledge that NBS is a very important and extraordinarily positive initiative especially for rare and serious inherited disorders; however, lessons learned from current NBS should guide the future of NBS as we enter the era of "omics" that will expand NBS for many other genetic disorders. In this article, I will first discuss new tools such as genomics and metabolomics for NBS. I will then turn to assessing how best to take advantage of new technical developments while considering the best interests of patients and the success of newborn screening...
May 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28487885/novel-de-novo-variant-in-ebf3-is-likely-to-impact-dna-binding-in-a-patient-with-a-neurodevelopmental-disorder-and-expanded-phenotypes-patient-report-in-silico-functional-assessment-and-review-of-published-cases
#20
Patrick R Blackburn, Sarah S Barnett, Michael T Zimmermann, Margot A Cousin, Charu Kaiwar, Filippo Pinto E Vairo, Zhiyv Niu, Matthew J Ferber, Raul A Urrutia, Duygu Selcen, Eric W Klee, Pavel N Pichurin
Pathogenic variants in EBF3 were recently described in three back-to-back publications in association with a novel neurodevelopmental disorder characterized by intellectual disability, speech delay, ataxia, and facial dysmorphisms. In this report, we describe an additional patient carrying a de novo missense variant in EBF3 (c.487C>T, p.(Arg163Trp)) that falls within a conserved residue in the zinc knuckle motif of the DNA binding domain. Without a solved structure of the DNA binding domain, we generated a homology-based atomic model and performed molecular dynamics simulations for EBF3, which predicted decreased DNA affinity for p...
May 2017: Cold Spring Harbor Molecular Case Studies
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