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Cold Spring Harbor Molecular Case Studies

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https://www.readbyqxmd.com/read/27900371/rapid-access-to-genetic-discoveries-underlying-human-disease
#1
Heidi L Rehm
No abstract text is available yet for this article.
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900370/a-patient-with-multisystem-dysfunction-carries-a-truncation-mutation-in-human-slc12a2-the-gene-encoding-the-na-k-2cl-cotransporter-nkcc1
#2
Eric Delpire, Lynne Wolfe, Bianca Flores, Rainelli Koumangoye, Cara C Schornak, Salma Omer, Barbara Pusey, Christopher Lau, Thomas Markello, David R Adams
This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phefs*2) and truncation of the carboxy-terminal tail of the cotransporter. Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900369/genomic-profiling-of-multiple-sequentially-acquired-tumor-metastatic-sites-from-an-exceptional-responder-lung-adenocarcinoma-patient-reveals-extensive-genomic-heterogeneity-and-novel-somatic-variants-driving-treatment-response
#3
Romi Biswas, Shaojian Gao, Constance M Cultraro, Tapan K Maity, Abhilash Venugopalan, Zied Abdullaev, Alexey K Shaytan, Corey A Carter, Anish Thomas, Arun Rajan, Young Song, Stephanie Pitts, Kevin Chen, Sara Bass, Joseph Boland, Ken-Ichi Hanada, Jinqiu Chen, Paul S Meltzer, Anna R Panchenko, James C Yang, Svetlana Pack, Giuseppe Giaccone, David S Schrump, Javed Khan, Udayan Guha
We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his 7-yr course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ∼1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900368/whole-exome-sequencing-reveals-an-inherited-r566x-mutation-of-the-epithelial-sodium-channel-%C3%AE-subunit-in-a-case-of-early-onset-phenotype-of-liddle-syndrome
#4
Linda M Polfus, Eric Boerwinkle, Richard A Gibbs, Ginger Metcalf, Donna Muzny, Narayanan Veeraraghavan, Megan Grove, Sanjay Shete, Stephanie Wallace, Dianna Milewicz, Neil Hanchard, James R Lupski, Syed Shahrukh Hashmi, Monesha Gupta-Malhotra
To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900367/whole-genome-sequencing-of-two-probands-with-hereditary-spastic-paraplegia-reveals-novel-splice-donor-region-variant-and-known-pathogenic-variant-in-spg11
#5
Allen Chi-Shing Yu, Anne Yin-Yan Chan, Wing Chi Au, Yun Shen, Ting Fung Chan, Ho-Yin Edwin Chan
Hereditary spastic paraplegias (HSPs) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of HSP subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with HSP symptoms, including bilateral lower limb weakness, unsteady gait, cognitive decline, dysarthria, and slurring of speech since the age of 14...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900366/exome-sequencing-reveals-germline-gain-of-function-egfr-mutation-in-an-adult-with-lhermitte-duclos-disease
#6
Samantha Colby, Lamis Yehia, Farshad Niazi, JinLian Chen, Ying Ni, Jessica L Mester, Charis Eng
Lhermitte-Duclos disease (LDD) is a rare cerebellar disorder believed to be pathognomonic for Cowden syndrome. Presently, the only known etiology is germline PTEN mutation. We report a 41-yr-old white female diagnosed with LDD and wild-type for PTEN. Exome sequencing revealed a germline heterozygous EGFR mutation that breaks a disulfide bond in the receptor's extracellular domain, resulting in constitutive activation. Functional studies demonstrate activation of ERK/AKT signaling pathways, mimicking PTEN loss-of-function downstream effects...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900365/genome-sequencing-in-a-case-of-niemann-pick-type-c
#7
Max Dougherty, John Lazar, Jason C Klein, Karina Diaz, Theodore Gobillot, Eli Grunblatt, Nicholas Hasle, Daniel Lawrence, Megan Maurano, Maria Nelson, Gregory Olson, Sanjay Srivatsan, Jay Shendure, C Dirk Keene, Thomas Bird, Marshall S Horwitz, Desiree A Marshall
Adult-onset Niemann-Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical ("variant" level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900364/analysis-of-intrapatient-heterogeneity-uncovers-the-microevolution-of-middle-east-respiratory-syndrome-coronavirus
#8
Donghyun Park, Hee Jae Huh, Yeon Jeong Kim, Dae-Soon Son, Hyo-Jeong Jeon, Eu-Hyun Im, Jong-Won Kim, Nam Yong Lee, Eun-Suk Kang, Cheol In Kang, Doo Ryeon Chung, Jin-Hyun Ahn, Kyong Ran Peck, Sun Shim Choi, Yae-Jean Kim, Chang-Seok Ki, Woong-Yang Park
Genome sequence analysis of Middle East respiratory syndrome coronavirus (MERS-CoV) variants from patient specimens has revealed the evolutionary dynamics and mechanisms of pathogenesis of the virus. However, most studies have analyzed the consensus sequences of MERS-CoVs, precluding an investigation of intrapatient heterogeneity. Here, we analyzed non-consensus sequences to characterize intrapatient heterogeneity in cases associated with the 2015 outbreak of MERS in South Korea. Deep-sequencing analysis of MERS-CoV genomes performed on specimens from eight patients revealed significant intrapatient variation; therefore, sequence heterogeneity was further analyzed using targeted deep sequencing...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900363/integration-of-genomics-and-histology-revises-diagnosis-and-enables-effective-therapy-of-refractory-cancer-of-unknown-primary-with-pdl1-amplification
#9
Stefan Gröschel, Martin Bommer, Barbara Hutter, Jan Budczies, David Bonekamp, Christoph Heining, Peter Horak, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Christina Geörg, Daniela Richter, Nicole Pfarr, Katrin Pfütze, Stephan Wolf, Peter Schirmacher, Dirk Jäger, Christof von Kalle, Benedikt Brors, Hanno Glimm, Wilko Weichert, Albrecht Stenzinger, Stefan Fröhling
Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900362/de-novo-phip-predicted-deleterious-variants-are-associated-with-developmental-delay-intellectual-disability-obesity-and-dysmorphic-features
#10
Emily Webster, Megan T Cho, Nora Alexander, Sonal Desai, Sakkubai Naidu, Mir Reza Bekheirnia, Andrea Lewis, Kyle Retterer, Jane Juusola, Wendy K Chung
Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900361/kbg-syndrome-involving-a-single-nucleotide-duplication-in-ankrd11
#11
Robert Kleyner, Janet Malcolmson, David Tegay, Kenneth Ward, Annette Maughan, Glenn Maughan, Lesa Nelson, Kai Wang, Reid Robison, Gholson J Lyon
KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900360/scn8a-mutation-in-a-child-presenting-with-seizures-and-developmental-delays
#12
Janet Malcolmson, Robert Kleyner, David Tegay, Whit Adams, Kenneth Ward, Justine Coppinger, Lesa Nelson, Miriam H Meisler, Kai Wang, Reid Robison, Gholson J Lyon
The SCN8A gene encodes the sodium voltage-gated channel alpha subunit 8. Mutations in this gene have been associated with early infantile epileptic encephalopathy type 13. With the use of whole-exome sequencing, a de novo missense mutation in SCN8A was identified in a 4-yr-old female who initially exhibited symptoms of epilepsy at the age of 5 mo that progressed to a severe condition with very little movement, including being unable to sit or walk on her own.
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900359/homozygous-inactivation-of-chek2-is-linked-to-a-familial-case-of-multiple-primary-lung-cancer-with-accompanying-cancers-in-other-organs
#13
Yoji Kukita, Jiro Okami, Noriko Yoneda-Kato, Ikuko Nakamae, Takeshi Kawabata, Masahiko Higashiyama, Junya Kato, Ken Kodama, Kikuya Kato
In clinical practice, there are a number of cancer patients with clear family histories, but the patients lack mutations in known familial cancer syndrome genes. Recent advances in genomic technologies have enhanced the possibility of identifying causative genes in such cases. Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer and had a history of uterine myoma. The latter had initially developed prostate cancer at the age of 59 and had a history of colon cancer...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27626069/evolution-of-a-flt3-tkd-mutated-subclone-at-meningeal-relapse-in-acute-promyelocytic-leukemia
#14
Tilmann Bochtler, Stefan Fröhling, Wilko Weichert, Volker Endris, Christian Thiede, Barbara Hutter, Michael Hundemer, Anthony D Ho, Alwin Krämer
Here, we report the case of an acute promyelocytic leukemia (APL) patient who-although negative for FLT3 mutations at diagnosis-developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27626068/integrated-tumor-and-germline-whole-exome-sequencing-identifies-mutations-in-mapk-and-pi3k-pathway-genes-in-an-adolescent-with-rosette-forming-glioneuronal-tumor-of-the-fourth-ventricle
#15
Frank Y Lin, Katie Bergstrom, Richard Person, Abhishek Bavle, Leomar Y Ballester, Sarah Scollon, Robin Raesz-Martinez, Andrew Jea, Sherri Birchansky, David A Wheeler, Stacey L Berg, Murali M Chintagumpala, Adekunle M Adesina, Christine Eng, Angshumoy Roy, Sharon E Plon, D Williams Parsons
The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27626067/testing-erbb2-p-l755s-kinase-domain-mutation-as-a-druggable-target-in-a-patient-with-advanced-colorectal-cancer
#16
Kyaw L Aung, Tracy L Stockley, Stefano Serra, Suzanne Kamel-Reid, Philippe L Bedard, Lillian L Siu
Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinical outcomes will be achieved by inhibiting these discovered genetic driver events with matched targeted drugs. This hypothesis is currently being tested in oncology clinics with variable early results. Herein, we present our experience with a case of advanced colorectal cancer (CRC) with an ERBB2 p...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27626066/a-novel-de-novo-mutation-in-atp1a3-and-childhood-onset-schizophrenia
#17
Niklas Smedemark-Margulies, Catherine A Brownstein, Sigella Vargas, Sahil K Tembulkar, Meghan C Towne, Jiahai Shi, Elisa Gonzalez-Cuevas, Kevin X Liu, Kaya Bilguvar, Robin J Kleiman, Min-Joon Han, Alcy Torres, Gerard T Berry, Timothy W Yu, Alan H Beggs, Pankaj B Agrawal, Joseph Gonzalez-Heydrich
We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium-potassium pump...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27626065/a-novel-tp53-kpna3-translocation-defines-a-de-novo-treatment-resistant-clone-in-osteosarcoma
#18
Kenneth S Chen, Woo Sun Kwon, Jiwoong Kim, Su Jin Heo, Hyo Song Kim, Hyo Ki Kim, Soo Hee Kim, Won Suk Lee, Hyun Cheol Chung, Sun Young Rha, Tae Hyun Hwang
Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27626064/a-de-novo-missense-mutation-in-zmynd11-is-associated-with-global-developmental-delay-seizures-and-hypotonia
#19
Abby M Moskowitz, Newell Belnap, Ashley L Siniard, Szabolcs Szelinger, Ana M Claasen, Ryan F Richholt, Matt De Both, Jason J Corneveaux, Chris Balak, Ignazio S Piras, Megan Russell, Amanda L Courtright, Sampath Rangasamy, Keri Ramsey, David W Craig, Vinodh Narayanan, Matt J Huentelman, Isabelle Schrauwen
Recently, mutations in the zinc finger MYND-type containing 11 (ZMYND11) gene were identified in patients with autism spectrum disorders, intellectual disability, aggression, and complex neuropsychiatric features, supporting that this gene is implicated in 10p15.3 microdeletion syndrome. We report a novel de novo variant in the ZMYND11 gene (p.Ser421Asn) in a patient with a complex neurodevelopmental phenotype. The patient is a 24-yr-old Caucasian/Filipino female with seizures, global developmental delay, sensorineural hearing loss, hypotonia, dysmorphic features, and other features including a happy disposition and ataxic gait similar to Angelman syndrome...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27551684/infantile-onset-spinocerebellar-ataxia-caused-by-compound-heterozygosity-for-twinkle-mutations-and-modeling-of-twinkle-mutations-causing-recessive-disease
#20
Sarah B Pierce, Suleyman Gulsuner, Gail A Stapleton, Tom Walsh, Ming K Lee, Jessica B Mandell, Augusto Morales, Rachel E Klevit, Mary-Claire King, R Curtis Rogers
Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c...
July 2016: Cold Spring Harbor Molecular Case Studies
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