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Cold Spring Harbor Molecular Case Studies

Benjamin Briggs, Kiely James, Shimul Chowdhury, Courtney Thornburg, Lauge Farnaes, David Dimmock, Stephen Kingsmore
Pediatric stroke can be either hemorrhagic or ischemic, with about 5% of hemorrhagic strokes being caused by genetic coagulopathies. We report an 8 month old presenting with a hemorrhagic stroke caused by severe Factor XIII deficiency (OMIM # 613225) in whom rapid whole genome sequencing identified a novel variant in the F13A1 gene c.1352_1353delAT (p.His451ArgfsTer29).
November 7, 2018: Cold Spring Harbor Molecular Case Studies
Winnie S Liang, Christopher Dardis, Adrienne Helland, Shobana Sekar, Jonathan Adkins, Lori Cuyugan, Daniel Enriquez, Sara Byron, Andrew S Little
Chordoma is a rare, orphan cancer arising from embryonal precursors of bone. Surgery and radiotherapy (RT) provide excellent local control, often at the price of significant morbidity due to the structures involved and the need for relatively high doses of RTare not typically curative; however, recurrence remains high. Although our understanding of the genetic changes that occur in chordoma is evolving rapidly, this knowledge has yet to translate into treatments. We performed comprehensive DNA (paired tumor/normal whole exome and shallow whole genome) and RNA (tumor whole transcriptome) next-generation sequencing analyses of archival sacral and clivus chordoma specimens...
October 15, 2018: Cold Spring Harbor Molecular Case Studies
John A Martignetti, Deep Pandya, Nimesh Nagarsheth, Ying Chen, Olga Camacho, Shannon Tomita, Michael Brodman, Charles Ascher-Walsh, Valentin Kolev, Samantha Cohen, Timothy Harkins, Eric Schadt, Boris Reva, Robert Sebra, Peter Dottino
Endometrial cancer is the most common gynecologic malignancy in industrialized countries and both its incidence and associated mortality are increasing. The "liquid biopsy" is becoming an important transformative precision oncology tool but barriers intrinsic to blood sampling have limited its use in early cancer detection. We hypothesized that using a more targeted sample for analysis, namely, a uterine lavage, should provide a more sensitive and specific diagnostic test for endometrial cancer. Using a custom 12-gene endometrial cancer panel, molecular analysis of uterine lavage fluid from an asymptomatic 67-year-old female without histopathologic evidence of pre-malignant lesions or cancer in her uterine tissue, revealed two oncogenic PTEN mutations...
October 9, 2018: Cold Spring Harbor Molecular Case Studies
Michael Zech, Daniel D Lam, Sandrina Weber, Riccardo Berutti, Kamila Poláková, Petra Havránková, Anna Fečíková, Tim M Strom, Evžen Růžička, Robert Jech, Juliane Winkelmann
Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio-whole-exome sequencing to identify a de novo essential splice-site variant (c...
September 27, 2018: Cold Spring Harbor Molecular Case Studies
Heidi Rehm
No abstract text is available yet for this article.
October 2018: Cold Spring Harbor Molecular Case Studies
Volkan Okur, Mythily Ganapathi, Ashley Wilson, Wendy K Chung
Two male siblings ages 15 and 10 yr old had similar features of intellectual disability, developmental delay, severe speech impairment, microcephaly, prematurity, and transient elevation of liver enzymes in infancy. Exome sequencing revealed one novel (c.65C>A; p.Ala22Asp) and one ultra-rare (c.3214T>C; p.Phe1072Leu) predicted damaging missense variant in trans in the gene encoding cytoplasmic valyl-tRNA synthetase ( VARS ). Biallelic variants in VARS have previously been associated with a neurodevelopmental disorder characterized by microcephaly, seizures, and cortical atrophy (NDMSCA; MIM #617802)...
October 2018: Cold Spring Harbor Molecular Case Studies
Monica Khurana, Donna Edwards, Frederic Rescorla, Caroline Miller, Ying He, Elizabeth Sierra Potchanant, Grzegorz Nalepa
Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant ( SPTA1 c...
October 2018: Cold Spring Harbor Molecular Case Studies
Marjorie P David, Rajkumar Venkatramani, Dolores H Lopez-Terrada, Angshumoy Roy, Ninad Patil, Kevin E Fisher
A 12-yr-old normocalcemic female treated for a ruptured ovarian juvenile granulosa cell tumor at an outside hospital presented for exploratory laparotomy and gross surgical debulking of pelvic recurrence. Morphologically, the tumor was composed of sheets and nests of small blue cells forming cysts of various sizes and focal mucinous differentiation. Epithelial membrane antigen (EMA), patchy inhibin, and strong and diffuse p53 immunoreactivity were also observed. A revised diagnosis of mixed sex cord stromal tumor with heterologous elements was favored because of the inhibin immunoreactivity...
October 2018: Cold Spring Harbor Molecular Case Studies
Gloria T Haskell, Mari Mori, Cynthia Powell, Timothy J Amrhein, Gillian I Rice, Lauren Bailey, Natasha Strande, Karen E Weck, James P Evans, Jonathan S Berg, Priya Kishnani
Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI...
October 2018: Cold Spring Harbor Molecular Case Studies
Jennifer Erdrich, Kurt B Schaberg, Michael S Khodadoust, Li Zhou, Andrew A Shelton, Brendan C Visser, James M Ford, Ash A Alizadeh, Stephen R Quake, Pamela L Kunz, John F Beausang
Neuroendocrine tumors (NETs) arising from tailgut cysts are a rare but increasingly reported entity with gene expression profiles that may be indicative of the gastrointestinal cell of origin. We present a case report describing the unique pathological and genomic characteristics of a tailgut cyst NET that metastasized to liver. The histologic and immunohistochemical findings were consistent with a well-differentiated NET. Genomic testing indicates a germline frameshift in BRCA1 and a few somatic mutations of unknown significance...
October 2018: Cold Spring Harbor Molecular Case Studies
Daniel C Koboldt, Rama D Kastury, Megan A Waldrop, Benjamin J Kelly, Theresa Mihalic Mosher, Heather McLaughlin, Don Corsmeier, Jonathan L Slaughter, Kevin M Flanigan, Kim L McBride, Lakshmi Mehta, Richard K Wilson, Peter White
We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression...
October 2018: Cold Spring Harbor Molecular Case Studies
Julia Wattacheril, Patrick R Shea, Saeed Mohammad, Cynthia Behling, Vimla Aggarwal, Laura A Wilson, Katherine P Yates, Joy Ito, Mark Fishbein, Nicholas Stong, Joel E Lavine, David B Goldstein
Diagnostic whole-exome sequencing has proven highly successful in a range of rare diseases, particularly early-onset genetic conditions. In more common conditions, however, exome sequencing for diagnostic purposes remains the exception. Here we describe a patient initially diagnosed with a common, complex liver disease, nonalcoholic fatty liver disease (NAFLD), who was determined to have Wilson disease (WD) upon research-related exome sequencing. The patient presented as a 14.5-yr-old adolescent with chronically elevated aminotransferases, normal ceruloplasmin, and histologic examination consistent with NAFLD with advanced fibrosis...
October 2018: Cold Spring Harbor Molecular Case Studies
Queenie K-G Tan, Heidi Cope, Rebecca C Spillmann, Nicholas Stong, Yong-Hui Jiang, Marie T McDonald, Jennifer A Rothman, Megan W Butler, Donald P Frush, Ralph S Lachman, Brendan Lee, Carlos A Bacino, Melanie J Bonner, Chad M McCall, Avani A Pendse, Nicole Walley, Vandana Shashi, Loren D M Pena
Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data...
October 2018: Cold Spring Harbor Molecular Case Studies
Andrew R Grant, Sarah E Hemphill, Lisa M Vincent, Heidi L Rehm
The ClinVar database is a useful tool for patients and physicians to view variant interpretations submitted by clinical and nonclinical labs. However, variants of uncertain significance (VUS) in ClinVar can pose a significant burden on patients. If possible, it is important to resolve discrepancies and uncertainties surrounding interpreted variants. Here we highlight a case of a family who received a report of a variant (c.622A>G, p.Ile208Val) in BRAF following prenatal RASopathy testing. The variant had been previously classified by our laboratory as a VUS, so the mother contacted our laboratory via ClinVar for further information, which prompted reevaluation of the variant...
October 2018: Cold Spring Harbor Molecular Case Studies
Charuta Furey, Prince Antwi, Daniel Duran, Andrew T Timberlake, Carol Nelson-Williams, Charles C Matouk, Michael L DiLuna, Murat Günel, Kristopher T Kahle
Hydrocephalus, a disorder of impaired cerebrospinal fluid (CSF) homeostasis, often results from an imbalance between CSF production and reabsorption. Rarely, hydrocephalus is the consequence of CSF hypersecretion in the context of diffuse villous hyperplasia of the choroid plexus (DVHCP). The limited genetic information in previously reported cases suggests a high prevalence of gains of Chromosome 9p in this disease, although the critical genes involved in DVHCP pathogenesis have not been identified. Here, we report a patient with syndromic hydrocephalus with DVHCP associated with a novel 9p24...
October 2018: Cold Spring Harbor Molecular Case Studies
Jason R Schwartz, Michael P Walsh, Jing Ma, Tamara Lamprecht, Shuoguo Wang, Gang Wu, Susana Raimondi, Brandon M Triplett, Jeffery M Klco
Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their development has remained elusive. Here we report next-generation sequencing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent...
October 2018: Cold Spring Harbor Molecular Case Studies
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
No abstract text is available yet for this article.
August 2018: Cold Spring Harbor Molecular Case Studies
Jeffrey W Craig, Bradley J Quade, Michael G Muto, Laura E MacConaill
An 85-yr-old woman was diagnosed with endometrial adenocarcinoma, endometrioid type. Imaging studies showed a large tumor distending the endometrial canal without evidence of local invasion or extrauterine disease. A hysterectomy was performed, followed by microscopic examination of longitudinal tissue sections. Histopathological review showed only focal myometrial invasion, equivocal lymphovascular invasion, and negative bilateral sentinel lymph nodes (FIGO stage IA). A sample of the tumor was submitted for molecular testing (massively parallel sequencing on OncoPanel) and was found to harbor an inversion on Chromosome 2 resulting in an EML4-ALK gene fusion...
August 2018: Cold Spring Harbor Molecular Case Studies
Marianne Dubard Gault, Diana Mandelker, Deborah DeLair, Carolyn R Stewart, Yelena Kemel, Margaret R Sheehan, Beth Siegel, Jennifer Kennedy, Vanessa Marcell, Angela Arnold, Hikmat Al-Ahmadie, Shakeel Modak, Mark Robson, Neerav Shukla, Stephen Roberts, Joseph Vijai, Sabine Topka, Alex Kentsis, Karen Cadoo, Maria Carlo, Alicia Latham Schwark, Ed Reznik, Renzo Dinatale, Jaclyn Hechtman, Ester Borras Flores, Sowmaya Jairam, Ciyu Yang, Yirong Li, Erol Can Bayraktar, Ozge Ceyhan-Birsoy, Liying Zhang, Wendy Kohlman, Joshua Schiffman, Zsofia Stadler, Kivanc Birsoy, Andrew Kung, Kenneth Offit, Michael F Walsh
Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with SDHA germline mutations. Cancer diagnoses for these patients carrying SDHA germline mutations included neuroblastoma ( n = 1), breast ( n = 1), colon ( n = 1), renal ( n = 1), melanoma and uterine ( n = 1), prostate ( n = 1), endometrial ( n = 1), bladder ( n = 1), and gastrointestinal stromal tumor (GIST) ( n = 2)...
August 2018: Cold Spring Harbor Molecular Case Studies
Jikui Guan, Susanne Fransson, Joachim Tetteh Siaw, Diana Treis, Jimmy Van den Eynden, Damini Chand, Ganesh Umapathy, Kristina Ruuth, Petter Svenberg, Sandra Wessman, Alia Shamikh, Hans Jacobsson, Lena Gordon, Jakob Stenman, Pär-Johan Svensson, Magnus Hansson, Erik Larsson, Tommy Martinsson, Ruth H Palmer, Per Kogner, Bengt Hallberg
Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options...
August 2018: Cold Spring Harbor Molecular Case Studies
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