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Cold Spring Harbor Molecular Case Studies

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https://www.readbyqxmd.com/read/28050602/exome-sequencing-identifies-de-novo-pathogenic-variants-in-fbn1-and-trps1-in-a-patient-with-a-complex-connective-tissue-phenotype
#1
Diane B Zastrow, Patricia A Zornio, Annika Dries, Jennefer Kohler, Liliana Fernandez, Daryl Waggott, Magdalena Walkiewicz, Christine M Eng, Melanie A Manning, Ellyn Farrelly, Paul G Fisher, Euan A Ashley, Jonathan A Bernstein, Matthew T Wheeler
Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants in FBN1 and TRPS1 were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28050601/progeroid-syndrome-patients-with-zmpste24-deficiency-could-benefit-when-treated-with-rapamycin-and-dimethylsulfoxide
#2
Baris Akinci, Shireesha Sankella, Christopher Gilpin, Keiichi Ozono, Abhimanyu Garg, Anil K Agarwal
Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28050600/histiocytoid-cardiomyopathy-and-microphthalmia-with-linear-skin-defects-syndrome-phenotypes-linked-by-truncating-variants-in-ndufb11
#3
Gillian Rea, Tessa Homfray, Jan Till, Ferran Roses-Noguer, Rachel J Buchan, Sam Wilkinson, Alicja Wilk, Roddy Walsh, Shibu John, Shane McKee, Fiona J Stewart, Victoria Murday, Robert W Taylor, Michael Ashworth, A John Baksi, Piers Daubeney, Sanjay Prasad, Paul J R Barton, Stuart A Cook, James S Ware
Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28050599/optic-atrophy-cataracts-lipodystrophy-lipoatrophy-and-peripheral-neuropathy-caused-by-a-de-novo-opa3-mutation
#4
Stephanie C Bourne, Katelin N Townsend, Casper Shyr, Allison Matthews, Scott A Lear, Raj Attariwala, Anna Lehman, Wyeth W Wasserman, Clara van Karnebeek, Graham Sinclair, Hilary Vallance, William T Gibson
We describe a woman who presented with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a c.235C > G p.(Leu79Val) variant in the optic atrophy 3 (OPA3) gene that was confirmed to be de novo. This report expands the severity of the phenotypic spectrum of autosomal dominant OPA3 mutations.
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28050598/alk-a-tyrosine-kinase-target-for-cancer-therapy
#5
REVIEW
Vijaykumar R Holla, Yasir Y Elamin, Ann Marie Bailey, Amber M Johnson, Beate C Litzenburger, Yekaterina B Khotskaya, Nora S Sanchez, Jia Zeng, Md Abu Shufean, Kenna R Shaw, John Mendelsohn, Gordon B Mills, Funda Meric-Bernstam, George R Simon
The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900371/rapid-access-to-genetic-discoveries-underlying-human-disease
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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