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Cold Spring Harbor Molecular Case Studies

Jianling Ji, Lishuang Shen, Moiz Bootwalla, Catherine Quindipan, Tatiana Tatarinova, Dennis T Maglinte, Jonathan Buckley, Gordana Raca, Sulagna C Saitta, Jaclyn A Biegel, Xiaowu Gai
BACKGROUND: Advancing the clinical utility of whole exome sequencing (WES) for patients with suspected genetic disorders is largely driven by bioinformatics approaches that streamline data processing and analysis. METHODS: Herein, we describe our experience with implementing a semi-automated and phenotype-driven WES diagnostic workflow, incorporating both the DRAGEN pipeline and the Exomiser variant prioritization tool, at an academic children's hospital with an ethnically diverse pediatric patient population...
February 12, 2019: Cold Spring Harbor Molecular Case Studies
Patrick Kiessling, Eric Dowling, Yajue Huang, Mai Lan Ho, Karthik Balakrishnan, Brenda Weigel, W Edward Highsmith, Zhiyv Niu, Lisa A Schimmenti
Gardner Syndrome describes a variant phenotype of familial adenomatous polyposis (FAP), characterized primarily by extracolonic lesions including osteomas, dental abnormalities, epidermal cysts, and soft tissue tumors. We describe a two-year old boy presenting with a 2 cm soft tissue mass of the forehead. Pathologic evaluation revealed a nuchal-type/Gardner-associated fibroma. Sequencing of the APC gene revealed a pathologic variant c.4666dupA. Parental sequencing of both blood and buccal tissue supported the de novo occurrence of this pathologic variant...
January 29, 2019: Cold Spring Harbor Molecular Case Studies
Elena Poddubskaya, Madina Baranova, Daria Allina, Marina Sekacheva, Lyudmila Makovskaia, Dmitriy Kamashev, Maria Suntsova, Viktoria Barbara, Irina Kochergina-Nikitskaya, Alexey Aleshin
Ovarian cancer is the fifth leading cause of cancer-related female mortalitiy and the most lethal gynecological cancer. In this report we present a rare case of recurrent granulosa cell tumor of the ovary. We describe a case of 26-year-old woman with progressive granulosa cell tumor of the right ovary despite multiple lines of therapy who underwent salvage therapy selection based on a novel bioinformatical decision support tool (Oncobox). This analysis generated a list of potentially actionable compounds, which when used clinically lead to partial response and later long-term stabilization of patient's disease...
January 17, 2019: Cold Spring Harbor Molecular Case Studies
Chu Jian Ma, Winston Lee, Nicholas Stong, Jana Zernant, Stanley Chang, David Goldstein, Takayuki Nagasaki, Rando Allikmets
ROM1 (retinal outer segment membrane protein 1) is a 351-amino acid integral membrane protein on chromosome 11q, with high structural similarity to PRPH2/RDS. Localized at the rims of photoreceptor outer segments (OS), it is required for the maintenance of OS structure. Here, we describe a case with a phenotypic manifestation of a homozygous single base pair deletion, c.712delC (p.Leu238Cysfs*78) in the ROM1 gene, resulting in early termination at exon 2. The variant was detected by whole exome sequencing (WES) in a 63-year-old Caucasian woman with late-onset pattern macular dystrophy...
January 10, 2019: Cold Spring Harbor Molecular Case Studies
David R Murdock, Yunyun Jiang, Michael Wangler, Michael M Khayat, Aniko Sabo, Jane Juusola, Kirsty McWalter, Krista S Schatz, Meral Gunay-Aygun, Richard A Gibbs
A 55-year-old male with severe intellectual disability, behavioral problems, kyphoscoliosis, and dysmorphic features was referred for a genetic evaluation. Chromosomal microarray, RASopathy gene panel, mitochondrial sequencing, and fragile X testing were all negative. Subsequent whole exome sequencing revealed a heterozygous, truncating variant in the AHDC1 gene, consistent with a diagnosis of Xia-Gibbs Syndrome (XGS). Review of his clinical history showed many classic dysmorphic and clinical features of XGS, but no major health issues in adulthood other than intellectual disability...
January 8, 2019: Cold Spring Harbor Molecular Case Studies
Erica S Tsang, Yaoqing Shen, Negar Chooback, Cheryl Ho, Martin Jones, Daniel J Renouf, Howard Lim, Sophie Sun, Stephen Yip, Erin Pleasance, Diana N Ionescu, Karen Mungall, Katayoon Kasaian, Yussanne Ma, Yongjun Zhao, Andrew Mungall, Richard Moore, Steven J M Jones, Marco Marra, Janessa Laskin
BACKGROUND: The Personalized OncoGenomics (POG) program at the British Columbia Cancer Agency integrates whole genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examined the subgroup of patients with metastatic non-small cell lung cancer (NSCLC) and report the prevalence of actionable targets, treatments, and outcomes. METHODS: We identified patients who were enrolled in the POG program between 2012-2016 who had a tumor biopsy and blood samples with comprehensive DNA (80X;40X normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer drivers and actionable targets...
December 4, 2018: Cold Spring Harbor Molecular Case Studies
Shannon Rego, Orit Dagan-Rosenfeld, Wenyu Zhou, M Reza Sailani, Patricia Limcaoco, Elizabeth Colbert, Monika Avina, Jessica Wheeler, Colleen Craig, Denis Salins, Hannes L Rost, Jessilyn Dunn, Tracey McLaughlin, Lars M Steinmetz, Jonathan A Bernstein, Michael P Snyder
Exome sequencing is increasingly utilized in both clinical and non-clinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study...
November 28, 2018: Cold Spring Harbor Molecular Case Studies
Anne M Rochtus, Sara Trowbridge, Richard D Goldstein, Beth Rosen Sheidley, Sanjay P Prabhu, Robin Haynes, Hannah C Kinney, Annapurna H Poduri
Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c...
February 2019: Cold Spring Harbor Molecular Case Studies
Jonathan Bender, Bailey Anderson, David A Bloom, Raja Rabah, Rhonda McDougall, Pankaj Vats, Rajen Mody
Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life. The presence of ETV6 and NTRK3 gene rearrangement is characteristic of IFS, which can be detected on routine fluorescence in situ hybridization (FISH) testing. Patients with IFS typically respond well to surgical resection and chemotherapy and have an overall survival of ∼90%. In this report, we outline the use of integrative clinical sequencing (ICS) including RNA-seq in a patient with refractory, metastatic IFS to reveal an unusual fusion ( LMNA-NTRK1 ), not detected by routine FISH testing, which was treated with oral crizotinib and resulted in a complete and durable long-term response...
February 2019: Cold Spring Harbor Molecular Case Studies
Mahesh Swaminathan, Sarah A Bannon, Mark Routbort, Kiran Naqvi, Tapan M Kadia, Koichi Takahashi, Yesid Alvarado, Farhad Ravandi-Kashani, Keyur P Patel, Richard Champlin, Hagop Kantarjian, Louise Strong, Courtney D DiNardo
Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene TP53 The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center...
February 2019: Cold Spring Harbor Molecular Case Studies
Simone Lipinski, Britt-Sabina Petersen, Matthias Barann, Agnes Piecyk, Florian Tran, Gabriele Mayr, Marlene Jentzsch, Konrad Aden, Stephanie T Stengel, Ulrich C Klostermeier, Vrunda Sheth, David Ellinghaus, Tobias Rausch, Jan O Korbel, Michael Nothnagel, Michael Krawczak, Christian Gilissen, Joris A Veltman, Michael Forster, Peter Forster, Clarence C Lee, Annette Fritscher-Ravens, Stefan Schreiber, Andre Franke, Philip Rosenstiel
Whole-genome and whole-exome sequencing of individual patients allow the study of rare and potentially causative genetic variation. In this study, we sequenced DNA of a trio comprising a boy with very-early-onset inflammatory bowel disease (veoIBD) and his unaffected parents. We identified a rare, X-linked missense variant in the NAPDH oxidase NOX1 gene (c.C721T, p.R241C) in heterozygous state in the mother and in hemizygous state in the patient. We discovered that, in addition, the patient was homozygous for a common missense variant in the CYBA gene (c...
February 2019: Cold Spring Harbor Molecular Case Studies
Laure Frésard, Stephen B Montgomery
High-throughput sequencing has ushered in a diversity of approaches for identifying genetic variants and understanding genome structure and function. When applied to individuals with rare genetic diseases, these approaches have greatly accelerated gene discovery and patient diagnosis. Over the past decade, exome sequencing has emerged as a comprehensive and cost-effective approach to identify pathogenic variants in the protein-coding regions of the genome. However, for individuals in whom exome-sequencing fails to identify a pathogenic variant, we discuss recent advances that are helping to reduce the diagnostic gap...
December 2018: Cold Spring Harbor Molecular Case Studies
David Claassen, Michelle Boals, Kevin M Bowling, Gregory M Cooper, Jennifer Cox, Michael Hershfield, Sara Lewis, Marcin Wlodarski, Mitchell J Weiss, Jeremie H Estepp
Diamond-Blackfan Anemia (DBA) is a rare polygenic disorder defined by congenital hypoplastic anemia with marked decrease or absence of bone marrow erythroid precursors. Identifying the specific genetic etiology is important for counseling and clinical management. A 6-yr-old boy with a clinical diagnosis of DBA has been followed by our pediatric hematology team since birth. His clinical course includes transfusion-dependent hypoplastic anemia and progressive autoimmune cytopenias. Genetic testing failed to identify a causative mutation in any of the classical DBA-associated genes...
December 2018: Cold Spring Harbor Molecular Case Studies
Brooke McKenna, Tanner Koomar, Kevin Vervier, Jamie Kremsreiter, Jacob J Michaelson
Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a case of male monozygotic twins with ASD and ID...
December 2018: Cold Spring Harbor Molecular Case Studies
Erica Sanford, Lauge Farnaes, Serge Batalov, Matthew Bainbridge, Susan Laubach, H Michael Worthen, Mari Tokita, Stephen F Kingsmore, John Bradley
X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase ( BTK ) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome...
December 2018: Cold Spring Harbor Molecular Case Studies
Haijiao Zhang, Aleksandra Paliga, Evie Hobbs, Stephen Moore, Susan Olson, Nicola Long, Kim-Hien T Dao, Jeffrey W Tyner
Genetic rearrangements involving FLT3 are rare and only recently have been detected in myeloid/lymphoid neoplasms associated with eosinophilia (MLN-eos) and chronic myeloproliferative disorders. Here we report two cases with FLT3 fusions in patients demonstrating mixed features of myelodysplastic/myeloproliferative neoplasms. In the first case, FLT3 was fused with a new fusion partner MYO18A in a patient with marrow features most consistent with atypical chronic myeloid leukemia; the second case involving ETV6 - FLT3 fusion was observed in a case with bone marrow features most consistent with chronic myelomonocytic leukemia...
December 2018: Cold Spring Harbor Molecular Case Studies
Daniel Diolaiti, Filemon S Dela Cruz, Gunes Gundem, Nancy Bouvier, Mathieu Boulad, Yanming Zhang, Alexander J Chou, Ira J Dunkel, Rashesh Sanghvi, Minita Shah, Heather Geiger, Sadia Rahman, Vanessa Felice, Kazimierz O Wrzeszczynski, Robert B Darnell, Cristina R Antonescu, Christopher A French, Elli Papaemmanuil, Andrew L Kung, Neerav Shukla
NUTM1 -rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1 -rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4-NUTM1 fusion gene defining a distinct clinicopathologic entity-NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature...
December 2018: Cold Spring Harbor Molecular Case Studies
Yanyan Qian, Bingbing Wu, Yulan Lu, Xinran Dong, Qian Qin, Wenhao Zhou, Huijun Wang
Epileptic encephalopathies are severe seizure disorders accompanied by intellectual disability. Whole-exome sequencing technology has enabled the discovery of genetic mutations responsible for a wide range of diseases, and severe epilepsy and neurodevelopmental diseases are often associated with rare de novo mutations. We identified a novel de novo frameshift mutation in the PPP3CA gene encoding calcium-dependent protein phosphatase (calcineurin) catalytic subunit A (c.1255_1256del, p.Ser419Cysfs*31) in an 11...
November 19, 2018: Cold Spring Harbor Molecular Case Studies
Christopher J Forlenza, Yanming Zhang, JinJuan Yao, Ryma Benayed, Peter Steinherz, Kavitha Ramaswamy, Rachel Kessel, Mikhail Roshal, Neerav Shukla
Acute Megakaryoblastic leukemia (AMKL) constitutes ~5-15% of cases of non-Down syndrome AML in children, and in the majority of cases, chimeric oncogenes resulting from recurrent gene rearrangements are identified. Based upon these rearrangements several molecular subsets have been characterized providing important prognostic information. One such subset includes a group of patients with translocations involving the KMT2A gene, which has been associated with various fusion partners in patients with AMKL. Here we report the molecular findings of a 2 year old girl with AMKL and t(11;17)(q23;25) found to have a KMT2A-SEPT9 fusion identified through targeted RNA sequencing...
November 19, 2018: Cold Spring Harbor Molecular Case Studies
Jenny J Ko, Jasleen Grewal, Tony Ng, Jean-Michel Lavoie, My Linh Thibodeau, Yaoqing Shen, Andrew J Mungall, Greg Taylor, Kasmintan A Schrader, Steven J M Jones, Christian Kollmannsberger, Janessa Laskin, Marco A Marra
INTRODUCTION: Thyroid-like follicular renal cell carcinoma (TLFRCC) is a rare cancer with few reports of metastatic disease. Little is known regarding genomic characteristics and therapeutic targets. We present the clinical, pathologic, genomic and transcriptomic analyses of a case of a 27-year-old male with TLFRCC who presented initially with bone metastases of unknown primary. METHODS: Genomic DNA from peripheral blood and metastatic tumor samples were sequenced...
November 16, 2018: Cold Spring Harbor Molecular Case Studies
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