Journals Cold Spring Harbor Molecular C...

Cold Spring Harbor Molecular Case Studies
Gabrielle Henslee, Christopher Williams, Pengfei Liu, Alison Bertuch
Telomere biology disorders (TBDs), largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD , which encodes the shelterin protein TPP1, is associated with both autosomal dominant and autosomal recessive TBDs. TPP1 is responsible for recruitment of telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase...
January 14, 2021: Cold Spring Harbor Molecular Case Studies
Cora Ricker, Andrew Woods, William Simonson, Melvin Lathara, Ganapati Srinivasa, Erin Rudzinski, Atiya Mansoor, Robert Irwin, Charles Keller, Noah E Berlow
Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar rhabdomyosarcoma is the most aggressive subtype with an 8% five-year disease-free survival rate when a chromosomal fusion is present, and 40% five-year disease-free survival rate when negative for a fusion event. The underlying biology of PAX-fusion negative alveolar rhabdomyosarcoma remains largely unexplored and is exceedingly rare in Li-Fraumeni syndrome patients...
January 12, 2021: Cold Spring Harbor Molecular Case Studies
Joshua Lieberman, Kyoko Kurosawa, Dhruba J SenGupta, Brad T Cookson, Stephen J Salipante, David Busch
The oral aerotolerant anaerobe Leptotrichia goodfellowii is an unusual cause of endocarditis and is amenable to treatment with beta lactam antibiotics. Since this organism is difficult to identify by conventional methods, molecular detection is a key diagnostic modality. Broad range 16S rDNA PCR followed by Sanger sequencing constitute the first-line molecular approach, yet, poor DNA quality, contaminating DNA, or low template quantity make identification challenging. Here we report a case of culture-negative, aortic and mitral valve endocarditis in a 66-year-old woman with a history of cardiomyopathy, atrial fibrillation with intracardiac pacer, poor dentition and recent tooth infection...
December 7, 2020: Cold Spring Harbor Molecular Case Studies
Lisa Welter, Liya Xu, Dillon McKinley, Angel E Dago, Rishvanth K Prabakar, Sara Restrepo-Vassalli, Kevin Xu, Mariam Rodriguez-Lee, Anand Kolatkar, Rafael Nevarez, Carmen Ruiz, Jorge Nieva, Peter Kuhn, James B Hicks
Currently, clinical characterization of metastatic breast cancer is based on tissue samples taken at time of diagnosis. However, tissue biopsies are invasive and tumors are continuously evolving, which indicates the need for minimal invasive longitudinal assessment of the tumor. Blood-based liquid biopsies provide minimal invasive means for serial sampling over the course of treatment and the opportunity to adjust therapies based on molecular markers. Here, we aim to identify cellular changes that occur in breast cancer over the lifespan of an affected patient through single-cell proteomic and genomic analysis of longitudinally sampled solid and liquid biopsies...
November 17, 2020: Cold Spring Harbor Molecular Case Studies
Francis P Lach, Sonia Singh, Kimberly A Rickman, Penelope D Ruiz, Raymond J Noonan, Kenneth B Hymes, Mark D DeLacure, Jennifer A Kennedy, Settara C Chandrasekharappa, Agata Smogorzewska
Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand crosslinks. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels, and point and splicing variants. Genotype-phenotype associations in FA are complex and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear...
November 10, 2020: Cold Spring Harbor Molecular Case Studies
Timothy Tidwell, Malia Deshotel, Janice Palumbos, Chris Miller, Pinar Bayrak-Toydemir, John C Carey
The archain 1 (ARCN1) gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in ARCN1 have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5- year-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the ARCN1-related syndrome caused by a novel de novo intronic variant...
November 5, 2020: Cold Spring Harbor Molecular Case Studies
Dong-Anh Khuong-Quang, Lauren M Brown, Marie Wong, Chelsea Mayoh, Alexandra Sexton-Oates, Amit Kumar, Mark Pinese, Sumanth Nagabushan, Loretta Lau, Louise E Ludlow, Andrew J Gifford, Michael Rodriguez, Jayesh Desai, Stephen B Fox, Michelle Haber, David S Ziegler, Jordan R Hansford, Glenn M Marshall, Mark J Cowley, Paul G Ekert
The identification of rearrangements driving expression of Neurotrophic Receptor Tyrosine Kinase (NTRK) family kinases in tumours has become critically important due to the availability of effective, specific inhibitor drugs. Whole genome sequencing (WGS) combined with RNA Sequencing (RNAseq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L-NTRK fusions identified in two paediatric central nervous system cancers and an extracranial solid tumour using WGS and RNAseq. These fusions arose either through a simple balanced rearrangement, or in the context of a complex chromoplexy event...
November 3, 2020: Cold Spring Harbor Molecular Case Studies
Lane T Savage, Stacie D Adams, Kiely N James, Shimul Chowdhury, Surender Rajasekaran, Jeremy W Prokop, Caleb P Bupp
Rapid whole genome sequencing (rWGS) allows for a diagnosis to be made quickly and impact medical management, particularly in critically ill children. Variants identified by this approach are often not identified using other testing methodologies, such as carrier screening or gene sequencing panels, targeted panels, or chromosomal microarrays. However, rWGS can identify variants of uncertain significance (VUS), which challenges clinicians in the rapid return of information to families. Here we present a case of the metabolic condition D-bifunctional protein deficiency in a neonate with epilepsy and hypotonia born to consanguineous parents...
October 28, 2020: Cold Spring Harbor Molecular Case Studies
Aizeddin A Mhanni, Cheryl R Greenberg, Elizabeth L Spriggs, Ronald Agatep, Reena Ray Sisk, Chitra Prasad
Isolated sulfite oxidase deficiency is a rare autosomal recessive inborn error of sulfur metabolism. Clinical features generally include devastating neurologic dysfunction, ectopia lentis, and increased urinary excretion of sulfite, thiosulfate, and S -sulfocysteine. Missed diagnosis is not unusual because of variability in the sensitivity of the urinary sulfite and thiosulfate screening test. We present clinical, biochemical, and molecular data on two unrelated patients with isolated sulfite oxidase deficiency...
December 2020: Cold Spring Harbor Molecular Case Studies
Ikeoluwa A Osei-Owusu, Alexis L Norris, Anya T Joynt, Jeremy Thorpe, Soonweng Cho, Elaine Tierney, Jonathan Schmidt, Louis Hagopian, Jacqueline Harris, Jonathan Pevsner
Chromosomal structural variation can cause severe neurodevelopmental and neuropsychiatric phenotypes. Here we present a nonverbal female adolescent with severe stereotypic movement disorder with severe problem behavior (e.g., self-injurious behavior, aggression, and disruptive and destructive behaviors), autism spectrum disorder, severe intellectual disability, attention deficit hyperactivity disorder, and global developmental delay. Previous cytogenetic analysis revealed balanced translocations present in the patient's apparently normal mother...
December 2020: Cold Spring Harbor Molecular Case Studies
Antara Afrin, Jeremy W Prokop, Adam Underwood, Katie L Uhl, Elizabeth A VanSickle, Roja Baruwal, Morgan Wajda, Surender Rajasekaran, Caleb Bupp
We present a male patient born at 38-wk gestation with rhizomelic shortening of extremities, hepatomegaly, ventriculomegaly, heart failure, severely depressed left ventricular function, biventricular hypertrophy, and biatrial enlargement. Additional physical findings included anteriorly displaced anus, vertebral anomalies, and brachydactyly. The patient's cardiac malformations led to persistent hypotension, sinus tachycardia, and multiorgan failure in the absence of arrhythmias. Rapid whole-exome sequencing was ordered on day of life (DOL) 8...
December 2020: Cold Spring Harbor Molecular Case Studies
Katherine G Roth, Isa Mambetsariev, Ravi Salgia
Tyrosine kinase inhibitors (TKIs) have transformed the standard of care in lung cancer. A number of TKIs have been discovered that specifically target oncogenes, including MET receptor tyrosine kinase. Second-generation MET TKIs are showing improved efficacy over first-generation TKIs. Herein, we report a case of a patient with metastatic lung adenocarcinoma harboring a MET exon 14 splice site mutation who has had prolonged disease control by a second-generation MET-TKI tepotinib. A 66-yr-old man was diagnosed with stage IV lung adenocarcinoma...
December 2020: Cold Spring Harbor Molecular Case Studies
Tammarah Sklarz, Stephanie N Hurwitz, Natasha L Stanley, Jane Juusola, Adam Bagg, Daria Babushok
Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation...
December 2020: Cold Spring Harbor Molecular Case Studies
Bing Xu, Anu Amallraja, Padmapriya Swaminathan, Rachel Elsey, Christel Davis, Stephanie Theel, Sarah Viet, Jason Petersen, Amy Krie, Gareth Davies, Casey B Williams, Erik Ehli, Tobias Meissner
Metastatic breast cancer is one of the leading causes of cancer related death in women. Limited studies have been done on the genomic evolution between primary and metastatic breast cancer. We reconstructed the genomic evolution through the sixteen year history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long term exposure to hormonal therapy. Genomic and transcriptome profiling was performed on primary breast tumor (2002), initial recurrence (2012) and liver metastasis (2015) samples...
October 2, 2020: Cold Spring Harbor Molecular Case Studies
Nobuyuki Takahashi, Vinodh N Rajapakse, Lorinc Pongor, Suresh Kumar, Camille Tlemsani, Rebecca Erwin-Cohen, Howard A Young, Stephen Hewitt, Jun S Wei, Javed Khan, Alejandro V Villarino, Jane B Trepel, Anish Thomas
Mismatch repair-deficient (dMMR) cancers generate a substantial number of immunogenic neoantigens, rendering them sensitive to immunotherapy. Yet, there is considerable variability in responses, and roughly one-half of dMMR cancers are refractory to immunotherapy. Here we study a patient with dMMR lung cancer refractory to immunotherapy. The tumor exhibited typical dMMR molecular features, including exceptionally high frameshift insertions and deletions (indels). Despite the treatment inducing abundant intratumoral T-cell infiltrates, it failed to elicit tumor regression, pointing to the T cells lacking cytotoxic activity...
October 2020: Cold Spring Harbor Molecular Case Studies
Lara Kamal, Sarah B Pierce, Christina Canavati, Amal Abu Rayyan, Tamara Jaraysa, Orit Lobel, Suhair Lolas, Barbara M Norquist, Grace Rabie, Fouad Zahdeh, Ephrat Levy-Lahad, Mary-Claire King, Moien N Kanaan
Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1 , in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1 , very few have been functionally characterized...
October 2020: Cold Spring Harbor Molecular Case Studies
Ajay Gupta, Jennifer A Belsky, Kathleen M Schieffer, Kristen Leraas, Elizabeth Varga, Sean D McGrath, Selene C Koo, Vincent Magrini, Richard K Wilson, Peter White, Elaine R Mardis, Kris R Jatana, Catherine E Cottrell, Bhuvana A Setty
Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. ETV6-NTRK3 fusions account for ∼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity...
October 2020: Cold Spring Harbor Molecular Case Studies
Erica Sanford, Marilyn C Jones, Matthew Brigger, Monia Hammer, Lucia Giudugli, Stephen F Kingsmore, David Dimmock, Matthew N Bainbridge
Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c...
October 2020: Cold Spring Harbor Molecular Case Studies
Alessia Pancaldi, Lei Peng, Daniel S Rhee, Emily Dunn, Jessica A Forcucci, Deborah Belchis, Christine A Pratilas
We report a case of a DICER1 -associated EWSR1 -rearranged malignant primitive neuroectodermal tumor (PNET) arising in a patient with DICER1 tumor predisposition syndrome. A 16-yr-old female with a history of multinodular goiter presented with a widely metastatic abdominal small round blue cell tumor with neuroectodermal differentiation. EWSR1 gene rearrangement was identified in the tumor by fluorescence in situ hybridization (FISH). Genetic analysis revealed biallelic pathogenic DICER1 variation. The patient was treated with an aggressive course of chemotherapy, surgery, and radiation with complete pathologic response...
October 2020: Cold Spring Harbor Molecular Case Studies
George Zanazzi, Benjamin L Liechty, Danielle Pendrick, Olga Krasnozhen-Ratush, Matija Snuderl, Jeffrey C Allen, James H Garvin, Mahesh M Mansukhani, Kevin A Roth, Susan J Hsiao
We report a case of a slow-growing, diffuse, infiltrating glioma in the right brainstem of a 9-yr-old boy. The tumor was negative by immunohistochemical staining for histone H3 K27M, BRAF V600E, and IDH1 R132H mutations. Fluorescence in situ hybridization did not reveal a BRAF duplication. Genomic profiling of the tumor, by DNA methylation array and cancer whole-exome and transcriptome sequencing, was performed. This analysis showed copy-number alterations, including gains of several chromosomes. In addition, a novel fusion involving the first 17 exons of FGFR2 fused to exon 2 of VPS35 was identified...
October 2020: Cold Spring Harbor Molecular Case Studies
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