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Cold Spring Harbor Molecular Case Studies

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https://www.readbyqxmd.com/read/29092958/wisp3-mutation-associated-with-pseudorheumatoid-dysplasia
#1
M Reza Sailani, James Chappell, Jingga Inlora, Linnea Lynch, Anil Narasimha, Safoura Mazroui, Amin Zia, Jonathan Bernstein, Omid Aryani, Michael P Snyder
Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness. Here we report genetic characterization of a consanguineous family segregating an uncharacterized from of skeletal dysplasia. Whole exome sequencing of four affected siblings and their parents identified a loss of function homozygous mutation in the WISP3 gene, leading to diagnosis of PPD in the affected individuals. The identified variant (chr6: 112382301; WISP3:c...
November 1, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29092957/molecular-characterisation-of-metastatic-pancreatic-neuroendocrine-tumours-pnets-using-whole-genome-and-transcriptome-sequencing
#2
Hui-Li Wong, Kevin C Yang, Yaoqing Shen, Eric Y Zhao, Jonathan M Loree, Hagen F Kennecke, Steve E Kalloger, Joanna M Karasinska, Howard J Lim, Andrew J Mungall, Xiaolan Feng, Janine M Davies, Kasmintan Schrader, Chen Zhou, Aly Karsan, Steven Jm Jones, Janessa Laskin, Marco A Marra, David F Schaeffer, Sharon M Gorski, Daniel J Renouf
Pancreatic neuroendocrine tumours (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials...
November 1, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29042446/clinical-and-metabolic-consequences-of-l-serine-supplementation-in-hereditary-sensory-and-autonomic-neuropathy-type-1c
#3
Mari Auranen, Jussi Toppila, Saranya Suriyanarayanan, Museer A Lone, Anders Paetau, Henna Tyynismaa, Thorsten Hornemann, Emil Ylikallio
Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment...
October 17, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28963436/novel-nr2f1-variants-likely-disrupt-dna-binding-molecular-modeling-in-two-cases-review-of-published-cases-genotype-phenotype-correlation-and-phenotypic-expansion-of-the-bosch-boonstra-schaaf-optic-atrophy-syndrome
#4
Charu Kaiwar, Michael T Zimmerman, Matthew J Ferber, Zhiyv Niu, Raul A Urrutia, Eric W Klee, Dusica Babovic-Vuksanovic
Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in NR2F1 gene. There are presently 28 cases of BBSOAS described in the literature. Its common features include developmental delay, intellectual disability, hypotonia, optic nerve atrophy, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity and thinning of the corpus callosum. Here we report two unrelated probands with novel, de novo, missense variants in NR2F1 The first is a 14-year-old male patient with hypotonia, intellectual disability, optic nerve hypoplasia, delayed bone age, short stature, and altered neurotransmitter levels on CSF testing...
September 28, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28877932/detection-and-genomic-characterization-of-a-mammary-like-adenocarcinoma
#5
Jasleen K Grewal, Peter Eirew, Martin Jones, Kenrry Chiu, Basile Tessier-Cloutier, Anthony N Karnezis, Aly Karsan, Andy Mungall, Chen Zhou, Stephen Yip, Anna V Tinker, Janessa Laskin, Marco Marra, Steven J M Jones
Whole-genome and transcriptome sequencing were performed to identify potential therapeutic strategies in the absence of viable treatment options for a patient initially diagnosed with vulvar adenocarcinoma. Genomic events were prioritized by comparison against variant distributions in the TCGA pan-cancer dataset, and complemented with detailed transcriptome sequencing and copy number analysis. These findings were considered against published scientific literature in order to evaluate the functional effects of potentially relevant genomic events...
September 6, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28864462/rapid-whole-genome-sequencing-identifies-a-novel-gabra1-variant-associated-with-west-syndrome
#6
Lauge Farnaes, Shareef A Nahas, Shimul Chowdhury, James Nelson, Serge Batalov, David M Dimmock, Stephen F Kingsmore
A 9-mo-old infant was admitted with infantile spasms that improved on administration of topiramate and steroids. He also had developmental delay, esotropia, and hypsarrhythmia on interictal electroencephalogram (EEG), and normal brain magnetic resonance imaging (MRI). West syndrome is the triad of infantile spasms, interictal hypsarrhythmia, and mental retardation. Rapid trio whole-genome sequencing (WGS) revealed a novel, likely pathogenic, de novo variant in the gene encoding γ-aminobutyric acid (GABA) type A receptor, α1 polypeptide (GABRA1 c...
September 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28864461/somatic-uniparental-disomy-of-chromosome-16p-in-hemimegalencephaly
#7
Nicole G Griffin, Kenneth D Cronin, Nicole M Walley, Christine M Hulette, Gerald A Grant, Mohamad A Mikati, Heather G LaBreche, Catherine W Rehder, Andrew S Allen, Peter B Crino, Erin L Heinzen
Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ∼70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein-coding regions of the genome...
September 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28864460/a-germline-fanca-alteration-that-is-associated-with-increased-sensitivity-to-dna-damaging-agents
#8
David C Wilkes, Verena Sailer, Hui Xue, Hongwei Cheng, Colin C Collins, Martin Gleave, Yuzhuo Wang, Francesca Demichelis, Himisha Beltran, Mark A Rubin, David S Rickman
Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies. A previous report revealed an association between an exceptional response to cisplatin treatment and a somatic loss of heterozygosity (LOH) of FANCA in a patient with metastatic prostate cancer who also harbored a germline FANCA variant (S1088F). Although germline FANCA mutations are the most frequent alterations in patients with Fanconi anemia, germline alterations are less common in prostate cancer...
September 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
#9
Ahmet Okay Çağlayan, Rabia Gonul Sezer, Hande Kaymakçalan, Ege Ulgen, Taner Yavuz, Jacob F Baranoski, Abdulkadir Bozaykut, Akdes Serin Harmanci, Yalim Yalcin, Mark W Youngblood, Katsuhito Yasuno, Kaya Bilgüvar, 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 as a high-throughput discovery tool for identifying novel disease-causing genes. We describe a male infant with primary dilated cardiomyopathy who was diagnosed using intrauterine echocardiography and found to progress to hypertrophic cardiomyopathy after birth...
September 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
#10
Elena Czink, Matthias Kloor, Benjamin Goeppert, Stefan Fröhling, Sebastian Uhrig, Tim F Weber, Jörn Meinel, Christian Sutter, Karl Heinz Weiss, Peter Schirmacher, Magnus von Knebel Doeberitz, Dirk Jäger, 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 reactivate antitumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/programmed death receptor ligand (PD-L1) pathway have shown clinical efficacy...
September 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
#11
Amber Hildreth, Kristen Wigby, Shimul Chowdhury, Shareef Nahas, Jaime Barea, Paulina Ordonez, Sergey Batalov, David Dimmock, Stephen 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 Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS)...
September 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
#12
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 mammalian target of rapamycin [mTOR] inhibitor everolimus) in advanced breast cancer patients have not utilized predictive genomic biomarker-based selection and have reported only modest improvement in the clinical outcome relative to standard of care...
September 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
#13
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 J Lim, Sophie Sun, Sean S Young, Aly Karsan, Yongjun Zhao, Andrew J Mungall, Richard A Moore, Daniel J Renouf, Karen Gelmon, Yussanne P Ma, Malcolm Hayes, Janessa Laskin, Marco A Marra, Kasmintan A Schrader, Steven J M Jones
We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-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 approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA...
September 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28835367/fgfr2-amplification-in-colorectal-adenocarcinoma
#14
Jamal H Carter, Catherine E Cottrell, Samantha McNulty, Katinka A Vingh-Conrad, Stephen Lamp, Jonathan W Heusel, Eric J Duncavage
FGFR2 is recurrently amplified in 5% of gastric cancers and 1-4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKI), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies...
August 23, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28802248/utility-of-rapid-whole-exome-sequencing-in-the-diagnosis-of-neonatal-niemann-pick-disease-type-c-presenting-with-fetal-hydrops-and-liver-failure
#15
Mersedeh Rohanizadegan, Sarah M Abdo, Anne O'Donnell-Luria, Ivana Mihalek, Peggy Chen, Marilyn Sanders, Kristen Leeman, Megan Cho, Christina Hung, Olaf Bodamer
Rapid whole exome sequencing (rWES) is increasingly used in critically ill newborn infants to inform about diagnosis, clinical management and prognosis. Here we report a male newborn infant with hydrops, pancytopenia and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure related morbidity and mortality and lack of diagnosis we employed rWES in the proband and both parents with a turn-around time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant in NPC1 suggestive of a diagnosis of Niemann Pick disease type C (NPC)...
August 11, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28729373/the-importance-of-managing-the-patient-and-not-the-gene-expanded-phenotype-of-gle1-associated-arthrogryposis
#16
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
#17
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
#18
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/28679694/understanding-physical-activity-in-cancer-patients-and-survivors-new-methodology-new-challenges-and-new-opportunities
#19
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
#20
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
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