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Cold Spring Harbor Molecular Case Studies

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https://www.readbyqxmd.com/read/29728376/reconciling-newborn-screening-and-a-novel-splice-variant-in-btd-associated-with-partial-biotinidase-deficiency-a-babyseq-project-case-report
#1
Jaclyn B Murry, Kalotina Machini, Ozge Ceyhan-Birsoy, Amy Kritzer, Joel B Krier, Matthew S Lebo, Shawn Fayer, Casie A Genetti, Grace E Vannoy, Timothy W Yu, Pankaj B Agrawal, Richard B Parad, Ingrid A Holm, Amy L McGuire, Robert C Green, Alan H Beggs, Heidi L Rehm, The BabySeq Project
Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance...
May 4, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29695406/a-novel-association-of-campomelic-dysplasia-with-hydrocephalus-due-to-an-unbalanced-chromosomal-translocation-upstream-of-sox9
#2
Prince Antwi, Christopher S Hong, Daniel Duran, Jin Sheng Chih, Weilai Dong, Michael DiLuna, Kristopher T Kahle
Campomelic dysplasia is a rare skeletal dysplasia characterized by Pierre-Robin sequence, craniofacial dysmorphism, shortening and angulation of long bones, tracheobronchomalacia, and occasionally sex reversal. The disease is due to mutations in SOX9 or chromosomal rearrangements involving the long arm of chromosome 17 harboring the SOX9 locus. SOX9, a transcription factor, is indispensible in establishing and maintaining neural stem cells in the CNS. We present a patient with angulation of long bones and external female genitalia on prenatal ultrasound who was subsequently found to harbor the chromosomal abnormality 46, XY, t(6;17) (p21...
April 25, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29602769/whole-exome-sequencing-identifies-germline-mutation-in-tp53-and-atrx-in-a-child-with-ge-nomically-aberrant-at-rt-and-her-mother-with-anaplastic-astrocytoma
#3
Kristiina Nordfors, Joonas Haapasalo, Ebrahim Afyounian, Joonas Tuominen, Matti Annala, Sergei Hayrynen, Ritva Karhu, Pauli Helen, Olli Lohi, Matti Nykter, Hannu Haapasalo, Kirsi Granberg
Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with the loss of ATRX protein expression...
March 30, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29588307/comprehensive-genomic-profiling-aids-in-treatment-of-a-metastatic-endometrial-cancer
#4
Jatinder Dhami, Kim M Hirshfield, Shridar Ganesan, Mira Hellmann, Veronica Rojas, Judith K Amorosa, Gregory M Riedlinger, Hua Zhong, Siraj M Ali, Dean Pavlick, Julia A Elvin, Lorna Rodriguez-Rodriguez
PURPOSE: FGFR-TACC fusions, including FGFR3-TACC3, have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. METHODS: Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol...
March 27, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29581140/transmission-of-a-tp53-germline-mutation-from-unaffected-male-carrier-associated-with-pediatric-glioblastoma-in-his-child-and-gestational-choriocarcinoma-in-his-female-partner
#5
Jennifer A Cotter, Linda Szymanski, Catherine Karimov, Lara Boghossian, Ashley Margol, Girish Dhall, Benita Tamrazi, G Isaac Varaprasathan, David M Parham, Alexander R Judkins, Jaclyn A Biegel
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53. LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-year-old boy with glioblastoma demonstrated a germline TP53 mutation with loss of heterozygosity for the short arm of chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-month-old daughter...
March 26, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29572239/identification-of-novel-mecom-gene-fusion-and-personalized-therapeutic-targets-through-integrative-clinical-sequencing-in-secondary-acute-myeloid-leukemia-in-a-patient-with-severe-congenital-neutropenia-a-case-report-and-literature-review
#6
James A Connelly, Rajen J Mody, Yi-Mi Wu, Dan R Robinson, Robert J Lonigro, Pankaj Vats, Erica Rabban, Bailey Anderson, Kelly Walkovich
Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents...
March 23, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29549119/the-case-for-early-use-of-rapid-whole-genome-sequencing-in-management-of-critically-ill-infants-late-diagnosis-of-coffin-siris-syndrome-in-an-infant-with-left-congenital-diaphragmatic-hernia-congenital-heart-disease-and-recurrent-infections
#7
Nathaly M Sweeney, Shareef A Nahas, Shimul Chowdhury, Miguel Del Campo, Marilyn C Jones, David P Dimmock, Stephen F Kingsmore, Rcigm Investigators
Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy number variants, and single gene mutations. CDH is the most expensive non-cardiac congenital defect: Management frequently requires implementation of Extracorporeal Membrane Oxygenation (ECMO), which increases management expenditures 2...
March 16, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29472286/a-novel-de-novo-capn5-mutation-in-a-patient-with-inflammatory-vitreoretinopathy-hearing-loss-and-developmental-delay
#8
Gabriel Velez, Alexander G Bassuk, Kellie A Schaefer, Brian Brooks, Lokesh Gakhar, MaryAnn Mahajan, Philip Kahn, Stephen H Tsang, Polly J Ferguson, Vinit B Mahajan
Mutations that activate the protease calpain-5 (CAPN5) cause a non-syndromic adult-onset autoinflammatory eye disease characterized by uveitis, altered synaptic signaling, retinal degeneration, neovascularization, and intraocular fibrosis. We describe a pediatric patient with severe inflammatory vitreoretinopathy accompanied by hearing loss and developmental delay associated with a novel, de novo CAPN5 missense mutation (c.865C>T, p.Arg289Trp) that shows greater hyperactivation of the calpain protease, indicating a genotype-phenotype correlation that links mutation severity to proteolytic activity and the possibility of earlier onset syndromic disease with auditory and neurological abnormalities...
February 22, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610397/the-era-of-precision-oncogenomics
#9
John C Carpten, Elaine R Mardis
No abstract text is available yet for this article.
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610396/precision-oncogenomics-in-pediatrics-a-personal-reflection
#10
Cindy Campbell, Jeffrey P Greenfield
Cindy Campbell, a bereaved parent who lost her son to a rare pediatric brain tumor, shares her experience and frustration over the lack of treatment options and minimal research funding in pediatric oncology. She invites Dr. Jeffrey P. Greenfield to reflect on the situation and share his professional experiences pertaining to advances in oncogenomics and pediatric brain tumors. They share a passion for making this technology available to all pediatric brain tumor patients in the future and using data to inform treatment protocols and improve outcomes...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610395/the-future-of-cancer-treatment-using-precision-oncogenomics
#11
Lukas D Wartman
Clinicians should soon have the opportunity to use precision oncogenomics to tailor the optimal cancer treatment to a specific patient. Precision oncogenomics will incorporate different sequencing platforms depending on the goal of the sequencing result. For example, the sequencing strategy used in immuno-oncology for the design of a tumor-specific vaccine may be different than that used by oncologists following a patient for clearance of mutations from circulating tumor DNA in the peripheral blood. I will provide a broad overview of several of the ways that precision oncogenomics is likely to influence the field of oncology over the next several years building off the experience at the Genomics Tumor Board at Washington University in St...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610394/bloom-syndrome-research-and-data-priorities-for-the-development-of-precision-medicine-as-identified-by-some-affected-families
#12
Mary Beth Campbell, Wesley C Campbell, James Rogers, Natalie Rogers, Zachary Rogers, Anne Marie van den Hurk, Annie Webb, Talon Webb, Paul Zaslaw
Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood of developing cancers of essentially all types, beginning at an early age. Cancer is the leading cause of death for persons with BS, and its early onset results in a reported median lifespan of <30 years. With fewer than 300 documented cases since BS was first described in 1954, its rarity has challenged progress in advancing both the care of and the cure for persons with BS...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610393/journey-from-oncologist-to-cancer-survivor-and-patient-advocate-in-the-era-of-precision-medicine
#13
Burton M Needles
In 2013, the American Association for Cancer Research (AACR) introduced the "Precision Medicine Series" of symposia. The goal of these conferences is to "highlight the incredible technology and advances in cancer research that together are enabling treatments that are precisely targeted to the unique molecular and genetic characteristics of an individual's cancer." This new series of AACR conferences reflects how patient treatment has evolved and continues to progress toward personalized treatments/medicine...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610392/personalized-oncogenomic-analysis-of-metastatic-adenoid-cystic-carcinoma-using-whole-genome-sequencing-to-inform-clinical-decision-making
#14
Manik Chahal, Erin Pleasance, Jasleen Grewal, Eric Zhao, Tony Ng, Erin Chapman, Martin R Jones, Yaoqing Shen, Karen L Mungall, Melika Bonakdar, Gregory A Taylor, Yussanne Ma, Andrew J Mungall, Richard A Moore, Howard Lim, Daniel Renouf, Stephen Yip, Steven J M Jones, Marco A Marra, Janessa Laskin
Metastatic adenoid cystic carcinomas (ACCs) can cause significant morbidity and mortality. Because of their slow growth and relative rarity, there is limited evidence for systemic therapy regimens. Recently, molecular profiling studies have begun to reveal the genetic landscape of these poorly understood cancers, and new treatment possibilities are beginning to emerge. The objective is to use whole-genome and transcriptome sequencing and analysis to better understand the genetic alterations underlying the pathology of metastatic and rare ACCs and determine potentially actionable therapeutic targets...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610391/application-of-genomics-to-identify-therapeutic-targets-in-recurrent-pediatric-papillary-thyroid-carcinoma
#15
Rebecca Ronsley, S Rod Rassekh, Yaoqing Shen, Anna F Lee, Colleen Jantzen, Jessica Halparin, Catherine Albert, Douglas S Hawkins, Shazhan Amed, Ralph Rothstein, Andrew J Mungall, David Dix, Geoffrey Blair, Helen Nadel, Steven J M Jones, Janessa Laskin, Marco A Marra, Rebecca J Deyell
Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole-genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610390/genomic-profiling-of-dedifferentiated-liposarcoma-compared-to-matched-well-differentiated-liposarcoma-reveals-higher-genomic-complexity-and-a-common-origin
#16
Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Wei-Lien Wang, Asrar Alimohamed, Curtis Gumbs, Latasha Little, Xingzhi Song, Barry W Feig, Christina L Roland, Jianhua Zhang, Robert S Benjamin, Patrick Hwu, Alexander J Lazar, P Andrew Futreal, Neeta Somaiah
Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes ( MDM2 , CDK4 , and YEATS2) and adipocytic differentiation factors ( HMGA2 and CPM) However, genomic changes associated with progression from WD to DD have not been well-defined...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610389/-fgfr1-tyrosine-kinase-domain-duplication-in-pilocytic-astrocytoma-with-anaplasia
#17
Leomar Y Ballester, Marta Penas-Prado, Norman E Leeds, Jason T Huse, Gregory N Fuller
We report the case of a 27-yr-old male with visual field loss who had a 4.9-cm complex cystic mass in the right occipital lobe. Histologic examination showed pilocytic astrocytoma (PA) with anaplasia, and molecular characterization revealed FGFR1 duplication with additional variants of unknown significance in several genes ( ARID1A, ARID1B, CHEK2, EPHA5, and MLL2 ). This is one of only a very few reported cases of anaplastic PA with characterization of molecular alterations.
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610388/clinically-actionable-mutation-profiles-in-patients-with-cancer-identified-by-whole-genome-sequencing
#18
Anna Schuh, Helene Dreau, Samantha J L Knight, Kate Ridout, Tuba Mizani, Dimitris Vavoulis, Richard Colling, Pavlos Antoniou, Erika M Kvikstad, Melissa M Pentony, Angela Hamblin, Andrew Protheroe, Marina Parton, Ketan A Shah, Zsolt Orosz, Nick Athanasou, Bass Hassan, Adrienne M Flanagan, Ahmed Ahmed, Stuart Winter, Adrian Harris, Ian Tomlinson, Niko Popitsch, David Church, Jenny C Taylor
Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610387/exceptional-response-to-everolimus-in-a-novel-tuberous-sclerosis-complex-2-mutation-associated-metastatic-renal-cell-carcinoma
#19
Samer Alsidawi, Pashtoon Murtaza Kasi
Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient with TSC2 -associated metastatic RCC with mutations H1620R and Y1650C who has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy...
April 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29449315/metaplastic-breast-cancer-in-a-patient-with-neurofibromatosis-type-1-and-somatic-loss-of-heterozygosity
#20
Lorena P Suarez-Kelly, Keiko Akagi, Julie W Reeser, Eric Samorodnitsky, Matthew Reeder, Amy Smith, Sameek Roychowdhury, David E Symer, William E Carson
Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1 , revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts...
April 2018: Cold Spring Harbor Molecular Case Studies
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