Journals Cold Spring Harbor Molecular C...

Cold Spring Harbor Molecular Case Studies
Katherine A Benson, Susan L Murray, Ross Doyle, Brendan Doyle, Anthony M Dorman, Denise Sadlier, Eoin Brennan, Margaret Large, Gianpiero L Cavalleri, Catherine Godson, Peter J Conlon
High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD)...
October 2020: Cold Spring Harbor Molecular Case Studies
Monica H Wojcik, Pankaj B Agrawal
Congenital anomalies, or structural birth defects, are common in the population, with 2-3% of infants estimated to have at least one major congenital malformation and countless others with minor malformations of lesser cosmetic or medical importance. As congenital malformations are major drivers of morbidity and mortality, representing the leading cause of infant mortality in the United States, there is substantial interest in understanding the underlying etiologies - particularly if modifiable causes may be identified or pre- or postnatal treatments can be offered...
August 21, 2020: Cold Spring Harbor Molecular Case Studies
Elena Busch, Simon Kreutzfeldt, Abbas Agaimy, Gunhild Mechtersheimer, Peter Horak, Benedikt Brors, Barbara Hutter, Martina Fröhlich, Sebastian Uhrig, Philipp Mayer, Evelin Schröck, Albrecht Stenzinger, Hanno Glimm, Dirk Jäger, Christoph Springfeld, Stefan Fröhling, Stefanie Zschäbitz
Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAF V600E -mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors...
August 2020: Cold Spring Harbor Molecular Case Studies
Erica Sanford, Terence Wong, Katarzyna A Ellsworth, Elizabeth Ingulli, Stephen F Kingsmore
Relatively little is known about phenotypic variability in nonsyndromic nephropathy associated with the gene encoding the WT1 transcription factor. We report a 12-mo-old female who presented with vomiting, diarrhea, and fatigue in the setting of renal failure and malignant hypertension. Trio ultra-rapid whole-genome sequencing identified a novel, likely pathogenic, de novo missense variant (c.485T > A, p.Val162Asp) in WT1 in 46 h, consistent with a diagnosis of nephrotic syndrome type 4 (NPHS4; OMIM 256370)...
August 2020: Cold Spring Harbor Molecular Case Studies
Ashley N Anderson, Danielle McClanahan, James Jacobs, Sophia Jeng, Myles Vigoda, Aurora S Blucher, Christina Zheng, Yeon Jung Yoo, Carolyn Hale, Xiaoming Ouyang, Daniel Clayburgh, Peter Andersen, Jeffrey W Tyner, Anna Bar, Olivia M Lucero, Justin J Leitenberger, Shannon K McWeeney, Molly Kulesz-Martin
Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES)...
August 2020: Cold Spring Harbor Molecular Case Studies
Josue A Flores Daboub, Johanes Fred Grimmer, Alice Frigerio, Whitney Wooderchak-Donahue, Ryan Arnold, Jeff Szymanski, Nicola Longo, Pinar Bayrak-Toydemir
Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in RASA1 are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity...
August 2020: Cold Spring Harbor Molecular Case Studies
Erica L Macke, Joel A Morales-Rosado, Aditi Gupta, Christopher T Schmitz, Teresa Kruisselbrink, Brendan Lanpher, Eric W Klee
Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor ( XPC ) are the cause of xeroderma pigmentosum, group C (MIM: 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14-15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics...
August 2020: Cold Spring Harbor Molecular Case Studies
Daniel Gamu, William T Gibson
Within histone H3, lysine 27 (H3K27) is one of the residues that functions as a molecular switch, by virtue of being subject to mutually exclusive post-translational modifications that have reciprocal effects on gene expression. Whereas acetylation of H3K27 is associated with transcriptional activation, methylation at this residue causes transcriptional silencing; these two modifications are mutually exclusive. Establishment of these epigenetic marks is important in defining cellular identity and for maintaining normal cell function, as evidenced by rare genetic disorders of epigenetic writers involved in H3K27 post-translational modification...
August 2020: Cold Spring Harbor Molecular Case Studies
Shiraj Sen, Ryuma Tanaka, Soumen Khatua, Wafik Zaky, Filip Janku, Marta Penas-Prado, Shiao-Pei Weathers, Amini Behrang, Jason Roszik, Vivek Subbiah
Although BRAF inhibition has demonstrated activity in BRAF V600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF V600 -mutated brain tumors...
August 2020: Cold Spring Harbor Molecular Case Studies
Jonathan Wong, Meaghan Wall, Gregory Philip Corboy, Nadine Taubenheim, Gareth Peter Gregory, Stephen Opat, Jake Shortt
T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%-20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach...
August 2020: Cold Spring Harbor Molecular Case Studies
Colin E Moore, Hector Monforte, Jamie K Teer, Yonghong Zhang, Sean Yoder, Andrew S Brohl, Damon Reed
Wilms tumor is the most common renal malignancy in children. In addition to staging, molecular risk stratification is being increasingly employed such as LOH in chromosomes 1 and 16. While genetic predisposition syndromes have been well characterized in some Wilms tumors, recent sequencing and biology efforts are expanding the classification of this malignancy. Here we present a case of siblings with remarkably similar presentations of bilateral Wilms tumor near 12 months of age. Thorough exam after the younger sibling was diagnosed did not reveal any signs to suggest one of the known Wilms predisposition syndromes...
July 22, 2020: Cold Spring Harbor Molecular Case Studies
Jack K Tung, Nastaran Neishaboori, Sigurdis Haraldsdottir, Carlos J Suarez
Although combination therapy with RAF and EGFR inhibitors have improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating Ras mutations, MAP2K mutations, and amplifications in BRAF, Ras, and EGFR. In this report, we describe a patient with BRAF-mutated CRC who acquired a N-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy...
July 15, 2020: Cold Spring Harbor Molecular Case Studies
Seth Devries, Monica Mulder, Jacob G Charron, Jeremy W Prokop, Paul R Mark
SLC6A1 is associated with an autosomal dominant early-onset seizure and epileptic encephalopathy associated with intellectual disability. We present a two-year-old girl with developmental delay and epilepsy, using a new computational filtering impact score to show the patients' variant ranks with other pathogenic variants. Genomic studies within the patient revealed a G443D variant of uncertain significance. Structural and evolutionary assessments establish this variant as a loss-of-function to the protein...
July 13, 2020: Cold Spring Harbor Molecular Case Studies
Yiming Zhong, Jeffery Schubert, Jinhua Wu, Feng Xu, Fumin Lin, Kajia Cao, Kristin Zelley, Minjie Luo, Jessica Foster, Kristina A Cole, Suzanne Macfarland, Adam C Resnick, Phillip B Storm, Marilyn M Li
PALB2 (partner and localizer of BRCA2) gene encodes a protein that co-localizes with BRCA2 in nuclear foci and likely permits the stable intra-nuclear localization and accumulation of BRCA2. PALB2 plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss of function disease mechanism. Biallelic PALB2 pathogenic variants have been described in autosomal recessive Fanconi Anemia. Heterozygous pathogenic variants in PALB2 are associated with increased risk for female and male breast cancer and pancreatic cancer (1-3)...
June 18, 2020: Cold Spring Harbor Molecular Case Studies
Chris Gunter, Wendy K Chung
No abstract text is available yet for this article.
June 2020: Cold Spring Harbor Molecular Case Studies
Jeffrey Ng, Eleanor Sams, Dustin Baldridge, Milinn Kremitzki, Daniel J Wegner, Tina Lindsay, Robert Fulton, F Sessions Cole, Tychele N Turner
We present a case of 9p- syndrome with a complex chromosomal event originally characterized by the classical karyotype approach as 46,XX,der(9)t(9;13)(p23;q13). We used advanced technologies (Bionano Genomics genome imaging and 10× Genomics sequencing) to characterize the location of the translocation and accompanying deletion on Chromosome 9 and duplication on Chromosome 13 with single-nucleotide breakpoint resolution. The translocation breakpoint was at Chr 9:190938 and Chr 13:50850492, the deletion at Chr 9:1-190938, and the duplication at Chr 13:50850492-114364328...
June 2020: Cold Spring Harbor Molecular Case Studies
Aixa Gonzalez Garcia, Julia Malone, Hong Li
Mosaicism in Cornelia de Lange syndrome (CdLS) has been reported in clinically diagnosed CdLS patients with negative molecular testing using blood as the specimen, particularly in the NIPBL gene. Here we report a novel mosaic variant in SMC1A identified in the buccal swab DNA of a patient with a mild CdLS phenotype. Our patient presented with global developmental delay, dysmorphic features, microcephaly, and short stature, with no limb defect. Face2Gene, a digital tool that analyzes facial morphology, demonstrated a 97% match between our patient and the CdLS gestalt...
June 2020: Cold Spring Harbor Molecular Case Studies
Daniel C Koboldt, Scott E Hickey, Bimal P Chaudhari, Theresa Mihalic Mosher, Tracy Bedrosian, Erin Crist, Stephen G Kaler, Kim McBride, Peter White, Richard K Wilson
Wilson disease is a medically actionable rare autosomal recessive disorder of defective copper excretion caused by mutations in ATP7B , one of two highly evolutionarily conserved copper-transporting ATPases. Hundreds of disease-causing variants in ATP7B have been reported to public databases; more than half of these are missense changes, and a significant proportion are presumed unequivocal loss-of-function variants (nonsense, frameshift, and canonical splice site). Current molecular genetic testing includes sequencing all coding exons (±10 bp) as well as deletion/duplication testing, with reported sensitivity of >98%...
June 2020: Cold Spring Harbor Molecular Case Studies
Alicia Jia, Elliot James, Henry Y Lu, Mehul Sharma, Bhavi P Modi, Catherine M Biggs, Kyla J Hildebrand, Alanna Chomyn, Stephanie Erdle, Hasandeep Kular, Stuart E Turvey
The innate immune system allows for rapid recognition of pathogens. Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade. Each TLR recognizes a distinct set of pathogen-associated molecular patterns (PAMPs) that encompass conserved microbial components such as lipopolysaccharides and flagellin. Upon binding of PAMPs and TLR activation, TLR intracellular domains initiate the oligomerization of the myeloid differentiation primary response 88 (MyD88), IRAK1, IRAK2, and IRAK4 signaling platform known as the Myddosome complex while also triggering the Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway...
June 2020: Cold Spring Harbor Molecular Case Studies
Ricardo Madrid, Sara R Guariglia, Andrea Haworth, William Korosh, Maureen Gavin, Gholson J Lyon
A 9-yr 8-mo-old right-handed female presented with a history of gait difficulties, which first became apparent at age 9 mo of age, along with slurred speech and hand tremors while holding a tray. Her past medical history was significant for global developmental delay, and she was attending fourth grade special education classes. On examination, she had an ataxic gait, dysarthria, absent deep tendon reflexes, and flexor plantar responses. There were no signs of optic atrophy or hearing loss. Nerve conduction studies were consistent with an axonal neuropathy...
June 2020: Cold Spring Harbor Molecular Case Studies
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