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Cold Spring Harbor Molecular Case Studies

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https://www.readbyqxmd.com/read/29970384/further-evidence-for-the-involvement-of-efl1-in-a-shwachman-diamond-like-syndrome-and-expansion-of-the-phenotypic-features
#1
Queenie K-G Tan, Heidi Cope, Rebecca C Spillmann, Nicholas Stong, Yong-Hui Jiang, Marie T McDonald, Jennifer A Rothman, Megan W Butler, Donald P Frush, Ralph S Lachman, Brendan Lee, Carlos A Bacino, Melanie J Bonner, Chad M McCall, Avani A Pendse, Nicole Walley, Udn Members, Vandana Shashi, Loren D M Pena
Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole exome sequencing data...
July 3, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29945942/reclassification-of-the-braf-p-ile208val-variant-by-case-level-data-sharing
#2
Andrew R Grant, Sarah E Hemphill, Lisa M Vincent, Heidi L Rehm
The ClinVar database is a useful tool for patients and physicians to view variant interpretations submitted by clinical and non-clinical labs. However, variants of uncertain significance (VUS) in ClinVar can pose a significant burden on patients. If possible, it is important to resolve discrepancies and uncertainties surrounding interpreted variants. Here we highlight a case of a family who received a report of a variant (c.622A>G, p.Ile208Val) in BRAF following prenatal RASopathy testing. The variant had been previously classified by our laboratory as a VUS, so the mother contacted our lab via ClinVar for further information which prompted re-evaluation of the variant...
June 26, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29907598/clinical-response-of-the-novel-activating-alk-i1171t-mutation-in-neuroblastoma-to-the-alk-inhibitor-ceritinib
#3
Jikui Guan, Susanne Fransson, Joachim Tetteh T Siaw, Diana Treis, Jimmy Van den Eynden, Damini Chand, Ganesh Umapathy, Petter Svenberg, Kristina Ruuth, Sandra Wessman, Alia Shamikh, Hans Jacobsson, Lena Gordon, Jakob Stenman, Erik Larsson, Par-Johan Svensson, Magnus Hansson, Tommy Martinsson, Per Kogner, Ruth H Palmer, Bengt Hallberg
Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options...
June 15, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29903892/novel-association-of-germline-de-novo-myh9-mutation-with-congenital-hemangioma
#4
Elena I Fomchenko, Daniel Duran, Sheng Chih Jin, Weilai Dong, E Zeynep Erson-Omay, Prince Antwi, August Allocco, Jonathan R Gaillard, Anita Huttner, Murat Gunel, Michael L DiLuna, Kristopher T Kahle
Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life due to concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 non-muscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score > 0...
June 14, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29895553/9p24-triplication-and-15q13-deletion-in-syndromic-hydrocephalus-with-diffuse-villous-hyperplasia-of-the-choroid-plexus
#5
Charuta Furey, Prince Antwi, Daniel Duran, Andrew T Timberlake, Carol Nelson-Williams, Charles C Matouk, Michael L DiLuna, Murat Günel, Kristopher T Kahle
Hydrocephalus, a disorder of impaired cerebrospinal fluid (CSF) homeostasis, often results from an imbalance between CSF production and reabsorption. Rarely, hydrocephalus is the consequence of CSF hypersecretion in the context of diffuse villous hyperplasia of the choroid plexus (DVHCP). The limited genetic information in previously reported cases suggests a high prevalence of gains of chromosome 9p in this disease, although the critical genes involved in DVHCP pathogenesis have not been identified. Here, we report a patient with syndromic hydrocephalus with DVHCP associated with a novel 9p24...
June 12, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29891567/clonal-dynamics-of-donor-derived-mds-after-unrelated-hct-for-high-risk-pediatric-b-lymphoblastic-leukemia
#6
Jason R Schwartz, Michael P Walsh, Jing Ma, Tamara Lamprecht, Shuoguo Wang, Gang Wu, Susana Raimondi, Brandon Triplett, Jeffery Klco
Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases and a unified mechanism for their development has remained elusive. Here we report next generation sequencing, including whole exome sequencing (WES), whole genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent...
June 11, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29848554/extremely-hypomorphic-and-severe-deep-intronic-variants-in-the-abca4-locus-result-in-varying-stargardt-disease-phenotypes
#7
Jana Zernant, Winston Lee, Takayuki Nagasaki, Frederick T Collison, Gerald A Fishman, Mette Bertelsen, Thomas Rosenberg, Peter Gouras, Stephen H Tsang, Rando Allikmets
Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ~75% of patients and only one mutation in ~15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 have been identified in the latter group. We extended our analyses of deep intronic ABCA4 variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2...
May 30, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29802153/co-occurrence-of-a-maternally-inherited-dnmt3a-duplication-and-a-paternally-inherited-pathogenic-variant-in-ezh2-in-a-child-with-growth-retardation-and-severe-short-stature-atypical-weaver-syndrome-or-evidence-of-a-dnmt3a-dosage-effect
#8
Katarzyna Polonis, Patrick R Blackburn, Raul Urrutia, Gwen A Lomberk, Teresa Kruisselbrink, Margot A Cousin, Nicole J Boczek, Nicole L Hoppman, Dusica Babovic-Vuksanovic, Eric W Klee, Pavel N Pichurin
Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes: EZH2 and NSD1 that cause Weaver and Sotos syndrome respectively, and the DNA methyltransferase (DNMT3A) gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in EZH2 (c...
May 25, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29798843/a-novel-de-novo-cdh1-germline-variant-aids-in-the-classification-of-c-terminal-e-cadherin-alterations-predicted-to-escape-nonsense-mediated-mrna-decay
#9
Kate Krempely, Rachid Karam
Most truncating CDH1 pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer and lobular breast cancer. However, transcripts containing carboxyl-terminal (C-terminal) premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay (NMD) pathway, and gastric and breast cancer risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing due to a personal history of invasive lobular breast cancer diagnosed at age 54, which identified the germline CDH1 nonsense alteration, c...
May 24, 2018: Cold Spring Harbor Molecular Case Studies
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
#10
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/29858379/erratum-whole-exome-sequencing-identifies-germline-mutation-in-tp53-and-atrx-in-a-child-with-genomically-aberrant-at-rt-and-her-mother-with-anaplastic-astrocytoma
#11
Kristiina Nordfors, Joonas Haapasalo, Ebrahim Afyounian, Joonas Tuominen, Matti Annala, Sergei Häyrynen, Ritva Karhu, Pauli Helén, Olli Lohi, Matti Nykter, Hannu Haapasalo, Kirsi J Granberg
No abstract text is available yet for this article.
June 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29858378/17p13-3-quadruplication-a-prenatal-and-postpartum-clinical-characterization-of-a-copy-number-variant
#12
Nicholas Farris, Helena Wu, Sara Said-Delgado, Barrie Suskin, Susan Klugman
Prenatal genetic testing has advanced rapidly in the past decade. However, not all results, including variants, are well understood. We report the finding of a 2.5-Mb gene region quadruplication of Chromosome 17p13.3. This region is well characterized for the deletion leading to Miller-Dieker syndrome but has an unclear replication phenotype. Invasive testing performed after ultrasound abnormalities were seen revealed the quadruplication sequence as well as a short segment (850 kb) with x5 copy number variation...
June 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29695406/a-novel-association-of-campomelic-dysplasia-and-hydrocephalus-with-an-unbalanced-chromosomal-translocation-upstream-of-sox9
#13
Prince Antwi, Christopher S Hong, Daniel Duran, Sheng Chih Jin, 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 central nervous system. 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...
June 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
#14
Nathaly M Sweeney, Shareef A Nahas, Shimul Chowdhury, Miguel Del Campo, Marilyn C Jones, David P Dimmock, Stephen F Kingsmore
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 noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2...
June 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
#15
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 nonsyndromic 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...
June 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29444904/mutation-in-an-alternative-transcript-of-cdkl5-in-a-boy-with-early-onset-seizures
#16
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 wk 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...
June 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29437776/rapid-whole-genome-sequencing-identifies-a-novel-aire-variant-associated-with-autoimmune-polyendocrine-syndrome-type-1
#17
Erica Sanford, Kelly Watkins, Shareef Nahas, Michael Gottschalk, Nicole G Coufal, Lauge Farnaes, David Dimmock, Stephen F Kingsmore
Autoimmune polyendocrine syndrome type 1 (APS-1; OMIM #240300), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator ( AIRE) gene. APS-1 is classically characterized by a triad of chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenocortical insufficiency. We report a 5-yr-old female who presented with symptoms of tetany due to hypocalcemia and was subsequently found to be secondary to hypoparathyroidism...
June 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29305346/a-de-novo-nonsense-mutation-in-asxl3-shared-by-siblings-with-bainbridge-ropers-syndrome
#18
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 yr and 15 yr) 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...
June 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29610397/the-era-of-precision-oncogenomics
#19
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
#20
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
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