Journals Cold Spring Harbor Molecular C...

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
Zoltán N Oltvai, Eric A Smith, Katie Wiens, Lawrence M Nogee, Mark Luquette, Andrew C Nelson, Kathryn A Wikenheiser-Brokamp
The ATP-binding cassette transporter member A3 (ABCA3) is a lipid transporter with a critical function in pulmonary surfactant biogenesis. Biallelic loss-of-function mutations in ABCA3 result in severe surfactant deficiency leading to neonatal respiratory failure with death in the first year of life. Herein, we describe a newborn with severe respiratory distress at birth progressing to respiratory failure requiring transplant. This patient was found to have a maternally inherited frameshift loss-of-function ABCA3 mutation and a paternally inherited synonymous variant in ABCA3 predicted to create a cryptic splice site...
June 2020: Cold Spring Harbor Molecular Case Studies
Shoji Ichikawa, Susan Prockop, Charlotte Cunningham-Rundles, Travis Sifers, Blair R Conner, Sitao Wu, Rachid Karam, Michael F Walsh, Elise Fiala
Reticular dysgenesis is a form of severe combined immunodeficiency (SCID) caused by biallelic pathogenic variants in AK2 Here we present the case of a boy diagnosed with SCID following a positive newborn screen (NBS). Genetic testing revealed a homozygous variant: AK2 c.330 + 5G > A. In silico analyses predicted weakened native donor splice site. However, this variant was initially classified as a variant of uncertain significance (VUS) given lack of direct evidence. To determine the impact on splicing, we analyzed RNA from the proband and his parents, using massively parallel RNA-seq of cloned RT-PCR products...
June 2020: Cold Spring Harbor Molecular Case Studies
Cagla Cömert, Lauren Brick, Debbie Ang, Johan Palmfeldt, Brandon F Meaney, Mariya Kozenko, Costa Georgopoulos, Paula Fernandez-Guerra, Peter Bross
Standardization of the use of next-generation sequencing for the diagnosis of rare neurological disorders has made it possible to detect potential disease-causing genetic variations, including de novo variants. However, the lack of a clear pathogenic relevance of gene variants poses a critical limitation for translating this genetic information into clinical practice, increasing the necessity to perform functional assays. Genetic screening is currently recommended in the guidelines for diagnosis of hypomyelinating leukodystrophies (HLDs)...
June 2020: Cold Spring Harbor Molecular Case Studies
Kenneth A Crawford, Noah E Berlow, Jennifer Tsay, Michael Lazich, Maria Mancini, Christopher Noakes, Tannie Huang, Charles Keller
In this case report we evaluate the genetics of and scientific basis of therapeutic options for a 14-yr-old male patient diagnosed with metastatic PAX3-FOXO1 fusion positive alveolar rhabdomyosarcoma. A distinguishing genetic feature of this patient was a germline RET C634F mutation, which is a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. Through sequential DNA and RNA sequencing analyses over the patient's clinical course, a set of gene mutations, amplifications, and overexpressed genes were identified and biological hypotheses generated to explore the biology of RET and coexisting signaling pathways in rhabdomyosarcoma...
June 2020: Cold Spring Harbor Molecular Case Studies
Wanxue Xu, Lacey Plummer, Richard Quiton, Francesca Swords, William F Crowley, Stephanie B Seminara, Ravikumar Balasubramanian
Biallelic pathogenic variants in RAB3GAP2 cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated...
May 6, 2020: Cold Spring Harbor Molecular Case Studies
Cecelia R Miller, Kristy Lee, Ruthann B Pfau, Shalini C Reshmi, Donald J Corsmeier, Sayaka Hashimoto, Ashita Dave-Wala, Vijayakumar Jayaraman, Daniel C Koboldt, Theodora Matthews, Danielle Mouhlas, Maggie Stein, Aimee McKinney, Tom Grossman, Benjamin J Kelly, Peter White, Vincent Magrini, Richard K Wilson, Elaine R Mardis, Catherine E Cottrell
Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristics of causal variants, and prevalence of mosaicism amongst disease-causing variants...
May 5, 2020: Cold Spring Harbor Molecular Case Studies
Isabelle Thiffault, Andrea Atherton, Bryce A Heese, Ahmed Abdelmoity, Kailash Pawar, Emily Farrow, Lee Zellmer, Neil Miller, Sarah Soden, Carol Saunders
Status epilepticus is not rare in critically ill intensive care unit patients, but its diagnosis is often delayed or missed. The mortality for convulsive status epilepticus is dependent on the underlying aetiologies and the age of the patients, and thus varies from study to study. In this context, effective molecular diagnosis in a pediatric patient with a genetically heterogeneous phenotype is essential. Homozygous or compound heterozygous variants in KPTN have been recently associated with a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures...
May 1, 2020: Cold Spring Harbor Molecular Case Studies
Anna Buser, Marjorie J Lindhurst, Hannah C Kondolf, Miranda R Yourick, Kim M Keppler-Noreuil, Julie C Sapp, Leslie G Biesecker
Proteus syndrome is mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G>A p.(Glu17Lys) pathogenic variant in AKT1, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 years of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p...
April 23, 2020: Cold Spring Harbor Molecular Case Studies
Calvin P Sjaarda, Beatrice Kaiser, Amy Jm McNaughton, Melissa L Hudson, Liam Harris-Lowe, Kyle Lou, Andrea Guerin, Muhammad Ayub, Xudong Liu
Pleiotropy and variable expressivity have been cited to explain the seemingly distinct neurodevelopmental disorders due to a common genetic etiology within the same family. Here we present a family with a de novo 1 Mb duplication involving 18 genes on chromosome 19. Within the family there are multiple cases of neurodevelopmental disorders including: Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, Intellectual Disability, and psychiatric disease in individuals carrying this Copy Number Variant (CNV)...
April 22, 2020: Cold Spring Harbor Molecular Case Studies
Fatima AbuBakr, Lauren Jeffries, Weizhen Ji, James M McGrath, Saquib Ali Lakhani
The transforming growth factor-β-activated kinase 1 (TAK1) encoded by mitogen-activated protein kinase kinase kinase 7 ( MAP3K7 ) is widely expressed and particpates in multiple molecular and cellular processes, including growth, differentiation, inflammation and apoptosis. Pathogenic variants in MAP3K7 have recently been associated with two disorders: cardiospondylocarpofacial syndrome (CSCFS) and frontometaphyseal dysplasia 2 (FMD2). To date, all small in-frame deletions and splice variants in MAP3K7 have been associated with CSCFS, while missense variants have been reported in both CSCFS and FMD2...
April 16, 2020: Cold Spring Harbor Molecular Case Studies
Cora A Ricker, Kenneth Crawford, Kevin Matlock, Melvin Lathara, Bernard Seguin, Erin R Rudzinski, Noah E Berlow, Charles Keller
Rhabdomyosarcoma (RMS) is the most common childhood soft-tissue sarcoma. The largest subtype of RMS is embryonal rhabdomyosarcoma (ERMS) and accounts for 53% of all RMS. ERMS typically occurs in the head and neck region, bladder, or reproductive organs and portends a promising prognosis when localized; however, when metastatic the 5-yr overall survival rate is ∼43%. The genomic landscape of ERMS demonstrates a range of putative driver mutations, and thus the recognition of the pathological mechanisms driving tumor maintenance should be critical for identifying effective targeted treatments at the level of the individual patients...
April 2020: Cold Spring Harbor Molecular Case Studies
Winston Y Lee, Ruthann B Pfau, Sarah M Choi, Jiong Yang, Hong Xiao, Eileen M Putnam, Russell Jh Ryan, Dale L Bixby, Lina Shao
We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome-like B-ALL (Ph-like B-ALL)...
April 2020: Cold Spring Harbor Molecular Case Studies
Patience Obasaju, Shubin Shahab, Emily Dunn, Daniel S Rhee, LiQun Jiang, Jeffrey S Dome, Alan D Friedman, Pedram Argani, Christine A Pratilas
Wilms tumor (WT) is the most common renal malignancy of childhood and accounts for 6% of all childhood malignancies. With current therapies, the 5-yr overall survival (OS) for children with unilateral favorable histology WT is greater than 85%. The prognosis is worse, however, for the roughly 15% of patients who relapse, with only 50%-80% OS reported in those with recurrence. Herein, we describe the extended and detailed clinical course of a rare case of a child with recurrent, pulmonary metastatic, favorable histology WT harboring a BRAF V600E mutation...
April 2020: Cold Spring Harbor Molecular Case Studies
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