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Cold Spring Harbor Molecular Case Studies

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
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
Lorena 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-year-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, chr17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts...
February 15, 2018: Cold Spring Harbor Molecular Case Studies
Dale L Bodian, John M Schreiber, Thierry Vilboux, Alina Khromykh, Natalie S Hauser
Infantile-onset epilepsies are a set of severe, heterogeneous disorders for which clinical genetic testing yields causative mutations in ~20-50% of affected individuals. We report the case of a boy presenting with intractable seizures at 2 weeks of age, for whom gene panel testing was unrevealing. Research-based whole genome sequencing of the proband and four unaffected family members identified a de novo mutation, NM_001323289.1:c.2828_2829delGA in CDKL5, a gene associated with X-linked early infantile epileptic encephalopathy 2...
February 14, 2018: Cold Spring Harbor Molecular Case Studies
Christopher A Miller, Sonika Dahiya, Tiandao Li, Robert Fulton, Matthew D Smyth, Gavin P Dunn, Joshua B Rubin, Elaine R Mardis
BACKGROUND: As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pre-genomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies...
February 13, 2018: Cold Spring Harbor Molecular Case Studies
Daniel R Owen, Hui-Li Wong, Melika Bonakdar, Martin Jones, Christopher S Hughes, Gregg B Morin, Steven J M Jones, Daniel J Renouf, Howard Lim, Janessa Laskin, Marco Marra, Stephen Yip, David F Schaeffer
Introduction ERBB2 amplification has been identified in approximately 5% of KRAS wild-type colorectal cancers. A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2 -amplified metastatic colorectal cancers resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2 -amplified colorectal cancer. Methods PCR-free whole genome sequencing was used to identify mutations, copy number alterations, structural variations and losses of heterozygosity...
February 8, 2018: Cold Spring Harbor Molecular Case Studies
Katherine E Miller, Benjamin Kelly, James Fitch, Nicole Ross, Matthew R Avenarius, Elizabeth Varga, Daniel C Koboldt, Daniel R Boue, Vincent Magrini, Scott L Coven, Jonathan L Finlay, Catherine E Cottrell, Peter White, Julie M Gastier-Foster, Richard K Wilson, Jeffrey Leonard, Elaine R Mardis
Gangliogliomas [WHO grade I] are rare tumors affecting the central nervous system and are most frequently observed in children. Genome sequencing of tumors is being utilized at an increasing rate in both research and clinical settings to characterize the genetic factors that drive tumorigenesis. Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13...
February 6, 2018: Cold Spring Harbor Molecular Case Studies
Erica Sanford, Kelly Watkins, Shareef Nahas, Michael Gottschalk, Nicole Coufal, Lauge Farnaes, David Dimmock, Stephen Kingsmore, Rcigm Investigators
Autoimmune polyendocrine syndrome type 1 (APS1; OMIM #240300), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene. APS1 is classically characterized by a triad of chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenocortical insufficiency. We report a five-year-old female who presented with symptoms of tetany due to hypocalcemia and was subsequently found to be secondary to hypoparathyroidism...
February 1, 2018: Cold Spring Harbor Molecular Case Studies
Agnes Balla, Kenneth J Hampel, Farrah Khan, Dara L Aisner, Nikoletta Sidiropoulos
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). These rearrangements occur because of a chromosomal inversion within the short arm of chromosome 2, which results in the formation of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene. While NSCLC transformation to SCLC is a rare phenomenon described in EGFR mutant cancers primarily after treatment with targeted therapy, it is exceedingly rare in ALK rearranged adenocarcinomas (Toyokawa et al...
January 9, 2018: Cold Spring Harbor Molecular Case Studies
Daniel C Koboldt, Theresa Mihalic Mosher, Benjamin J Kelly, Emily Sites, Dennis Bartholomew, Scott E Hickey, Kim McBride, Richard K Wilson, Peter White
Two sisters (ages 16 y. and 15 y.) have been followed by our clinical genetics team for several years. Both girls have severe intellectual disability, hypotonia, seizures, and distinctive craniofacial features. The parents are healthy, and have no other children. Oligo array, fragile X testing, and numerous single-gene tests were negative. All four family members underwent research exome sequencing, which revealed a heterozygous nonsense mutation in ASXL3 (p.R1036X) that segregated with disease. Exome data and independent Sanger sequencing confirmed that the variant is de novo, suggesting possible germline mosaicism in one parent...
January 5, 2018: Cold Spring Harbor Molecular Case Studies
Danielle R Azzariti, Erin Rooney Riggs, Annie Niehaus, Laura Lyman Rodriguez, Erin M Ramos, Brandi Kattman, Melissa J Landrum, Christa L Martin, Heidi L Rehm
Data sharing between laboratories, clinicians, researchers, and patients is essential for improvements and standardization in genomic medicine; encouraging genomic data sharing (GDS) is a key activity of the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen). The ClinGen initiative is dedicated to evaluating the clinical relevance of genes and variants for use in precision medicine and research. Currently, data originating from each of the aforementioned stakeholder groups is represented in ClinVar, a publicly available repository of genomic variation, and its relationship to human health hosted by the National Center for Biotechnology Information at the NIH...
February 2018: Cold Spring Harbor Molecular Case Studies
Siren Berland, Trine L Toft-Bertelsen, Ingvild Aukrust, Jan Byska, Marc Vaudel, Laurence A Bindoff, Nanna MacAulay, Gunnar Houge
Aquaporin-4, encoded by AQP4 , is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. Using genomic copy-number analysis and trio-exome sequencing, we investigated a male patient with intellectual disability, hearing loss, and progressive gait dysfunction and found a de novo missense change Ser111Thr in AQP4 as the only suspicious finding. Perinatally, signs of brain ischemia were detected in relation to acute collapse 2 h after birth that resolved a few days later...
February 2018: Cold Spring Harbor Molecular Case Studies
Jacqueline G Lu, Juliet Bishop, Sarah Cheyette, Igor B Zhulin, Su Guo, Nara Sobreira, Steven E Brenner
Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in PRRT2 (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel PRRT2 pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS)...
February 2018: Cold Spring Harbor Molecular Case Studies
Salem Alawbathani, Amit Kawalia, Mert Karakaya, Janine Altmueller, Peter Nuernberg, Sebahattin Cirak
Rare diseases are often misdiagnosed or receive a delayed diagnosis and thus unfortunately affected individuals may not receive optimal medical management. Here, we report a case of two siblings with a severe phenotype of progressive pseudorheumatoid dysplasia (PPD). Their onset of symptoms began at the age of 3 years. Both were neglected in the past and the patients presented with a very severe phenotype and unmitigated natural history. PPD is a rare autosomal recessive skeletal dysplasia characterized by progressive joint stiffness, swelling and pain...
December 19, 2017: Cold Spring Harbor Molecular Case Studies
Ecaterina Ileana Dumbrava, Funda Meric-Bernstam
The next-generation sequencing (NGS), also known as massively parallel sequencing, is rapidly being incorporated into oncology practice. With increasing numbers of genes tested, interpretation of genomic reports and selecting treatments based on the tumor's genomic analysis becomes more and more complicated for the treating oncologist. To help guide personalized treatments in oncology, The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT) at MD Anderson Cancer Center has developed a knowledge base, available at https://personalizedcancertherapy...
December 6, 2017: Cold Spring Harbor Molecular Case Studies
Volkan Okur, Wendy K Chung
Mutations in hereditary cancer syndromes account for a modest fraction of all cancers; however, identifying patients with these germline mutations offers tremendous health benefits to both patients and their family members. There are about 60 genes that confer a high lifetime risk of specific cancers, and this information can be used to tailor prevention, surveillance, and treatment. With advances in next-generation sequencing technologies and the elimination of gene patents for evaluating genetic information, we are now able to analyze multiple genes simultaneously, leading to the widespread clinical use of gene panels for germline cancer testing...
November 2017: Cold Spring Harbor Molecular Case Studies
Akemi J Tanaka, Megan T Cho, Rebecca Willaert, Kyle Retterer, Yuri A Zarate, Katie Bosanko, Vikki Stefans, Kimihiko Oishi, Amy Williamson, Golder N Wilson, Alice Basinger, Tina Barbaro-Dieber, Lucia Ortega, Susanna Sorrentino, Melissa K Gabriel, Ilse J Anderson, Maria J Guillen Sacoto, Rhonda E Schnur, Wendy K Chung
Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 ( EBF3 ) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development...
November 2017: Cold Spring Harbor Molecular Case Studies
Ren-Chin Wu, Ema Veras, Jeffrey Lin, Emily Gerry, Asli Bahadirli-Talbott, Alexander Baras, Ayse Ayhan, Ie-Ming Shih, Tian-Li Wang
Synchronous endometrial and ovarian (SEO) carcinomas involve endometrioid neoplasms in both the ovary and uterus at the time of diagnosis. Patients were traditionally classified as having independent primary SEO lesions or as having metastatic endometrioid carcinoma. Recent studies have supported that SEO tumors result from the dissemination of cells from one organ site to another. However, whether this can be considered a "metastasis" or "dissemination" remains unclear. In this report, we performed whole-exome sequencing of tumor samples from a woman with well-differentiated endometrioid SEO tumors and a clinical "recurrent" poorly differentiated peritoneal tumor that was diagnosed 8 years after the complete resection of the SEO tumors...
November 2017: Cold Spring Harbor Molecular Case Studies
M Reza Sailani, James Chappell, Jingga Inlora, Linnea Lynch, Anil Narasimha, Safoura Mazroui, Amin Zia, Jonathan Bernstein, Omid Aryani, Michael P Snyder
Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness. Here we report genetic characterization of a consanguineous family segregating an uncharacterized from of skeletal dysplasia. Whole exome sequencing of four affected siblings and their parents identified a loss of function homozygous mutation in the WISP3 gene, leading to diagnosis of PPD in the affected individuals. The identified variant (chr6: 112382301; WISP3:c...
November 1, 2017: Cold Spring Harbor Molecular Case Studies
Hui-Li Wong, Kevin C Yang, Yaoqing Shen, Eric Y Zhao, Jonathan M Loree, Hagen F Kennecke, Steve E Kalloger, Joanna M Karasinska, Howard J Lim, Andrew J Mungall, Xiaolan Feng, Janine M Davies, Kasmintan Schrader, Chen Zhou, Aly Karsan, Steven Jm Jones, Janessa Laskin, Marco A Marra, David F Schaeffer, Sharon M Gorski, Daniel J Renouf
Pancreatic neuroendocrine tumours (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials...
November 1, 2017: Cold Spring Harbor Molecular Case Studies
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