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Human Mutation

Cristina Fortuno, Paul James, Amanda B Spurdle
Pathogenic germline variants in TP53 predispose carriers to the multi-cancer Li-Fraumeni syndrome (LFS).  Widespread multigene panel testing is identifying TP53 pathogenic variants in breast cancer patients outside the strict clinical criteria recommended for LFS testing. We aimed to assess frequency and clinical implications of TP53 pathogenic variants in breast cancer cohorts ascertained outside LFS. Classification of TP53 germline variants reported in 59 breast cancer studies, and publicly available population control sets was reviewed and identified evidence for misclassification of variants...
September 21, 2018: Human Mutation
Harindra Arachchi, Monica H Wojcik, Benjamin Weisburd, Julius O B Jacobsen, Elise Valkanas, Samantha Baxter, Alicia B Byrne, Anne H O'Donnell-Luria, Melissa Haendel, Damian Smedley, Daniel G MacArthur, Anthony A Philippakis, Heidi L Rehm
Rare disease investigators constantly face challenges in identifying additional cases to build evidence for gene-disease causality. The Matchmaker Exchange (MME) addresses this limitation by providing a mechanism for matching patients across genomic centers via a federated network. The MME has revolutionized searching for additional cases by making it possible to query across institutional boundaries, so that what was once a laborious and manual process of contacting researchers is now automated and computable...
September 21, 2018: Human Mutation
Konstantin Weber-Lassalle, Philipp Harter, Jan Hauke, Corinna Ernst, Stefan Kommoss, Frederik Marmé, Nana Weber-Lassalle, Katharina Prieske, Dimo Dietrich, Julika Borde, Esther Pohl-Rescigno, Alexander Reuss, Beyhan Ataseven, Christoph Engel, Julia C Stingl, Rita K Schmutzler, Eric Hahnen
The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients´ ovarian cancer in 3 out of 6 TP53-positive cases. In 3 out of 6 patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice...
September 14, 2018: Human Mutation
Leslie J Burke, Jan Sevcik, Gaetana Gambino, Emma Tudini, Eliseos J Mucaki, Ben C Shirley, Philip Whiley, Michael T Parsons, Kim De Leeneer, Sara Gutiérrez-Enríquez, Marta Santamariña, Sandrine M Caputo, Elizabeth Santana Dos Santos, Jana Soukupova, Marketa Janatova, Petra Zemankova, Klara Lhotova, Lenka Stolarova, Mariana Borecka, Alejandro Moles-Fernández, Siranoush Manoukian, Bernardo Bonanni, Stacey L Edwards, Marinus J Blok, Thomas van Overeem Hansen, Maria Rossing, Orland Diez, Ana Vega, Kathleen B M Claes, David E Goldgar, Etienne Rouleau, Paolo Radice, Paolo Peterlongo, Peter K Rogan, Maria Caligo, Amanda B Spurdle, Melissa A Brown
The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in non-coding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6000 early-onset and/or familial breast cancer cases collected by the ENIGMA consortium for sequence variants in the 5' non-coding regions of breast cancer susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0...
September 11, 2018: Human Mutation
Marta Llorens-Agost, Janna Luessing, Amandine van Beneden, John Eykelenboom, Dawn O'Reilly, Louise S Bicknell, John J Reynolds, Marianne van Koegelenberg, Matthew E Hurles, Angela F Brady, Andrew P Jackson, Grant S Stewart, Noel F Lowndes
Ataxia Telangiectasia and Rad3 related (ATR) is one of the main regulators of the DNA damage response. It coordinates cell cycle checkpoint activation, replication fork stability, restart and origin firing to maintain genome integrity. Mutations of the ATR gene have been reported in Seckel patients, who suffer from a rare genetic disease characterized by severe microcephaly and growth retardation. Here, we report the case of a Seckel patient with compound heterozygous mutations in ATR. One allele has an intronic mutation affecting splicing of neighbouring exons, the other an exonic missense mutation, producing the variant p...
September 10, 2018: Human Mutation
Ahmad N Abou Tayoun, Tina Pesaran, Marina T DiStefano, Andrea Oza, Heidi L Rehm, Leslie G Biesecker, Steven M Harrison
The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide decision-making pathways assimilating information about variant type, its location, or any additional evidence for the likelihood of a true null effect...
September 7, 2018: Human Mutation
Martina Proietti Onori, Balwina Koopal, David B Everman, Jessica D Worthington, Julie R Jones, Melissa A Ploeg, Edwin Mientjes, Bregje W van Bon, Tjitske Kleefstra, Howard Schulman, Steven A Kushner, Sébastien Küry, Ype Elgersma, Geeske M van Woerden
The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function...
September 5, 2018: Human Mutation
Alexander J Abrams, Flavia Fontanesi, Natalie Bl Tan, Elena Buglo, Ion J Campeanu, Andrew J Kornberg, Dean G Phelan, Zornitza Stark, Stephan Zuchner
Recessive SLC25A46 mutations cause a spectrum of neurodegenerative disorders with optic atrophy as a core feature. We report a patient with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy, who is on the mildest end of the phenotypic spectrum. By studying seven different non-truncating mutations, we found that the stability of the SLC25A46 protein inversely correlates with the severity of the disease and the patient's variant does not markedly destabilize the protein. SLC25A46 belongs to the mitochondrial transporter family, but it is not known to have transport function...
September 3, 2018: Human Mutation
Dídac Casas-Alba, Antonio Martínez-Monseny, Rosa M Pino-Ramírez, Laia Alsina, Esperanza Castejón, Sergi Navarro-Vilarrubí, Belén Pérez-Dueñas, Mercedes Serrano, Francesc Palau, Alfredo García-Alix
Hyaline fibromatosis syndrome (HFS) is the unifying term for infantile systemic hyalinosis and juvenile hyaline fibromatosis. HFS is a rare autosomal recessive disorder of the connective tissue caused by mutations in the gene for anthrax toxin receptor-2 (ANTXR2). It is characterized by abnormal growth of hyalinized fibrous tissue with cutaneous, mucosal, osteoarticular, and systemic involvement. We review the 84 published cases and their molecular findings, aiming to gain insight into the clinical features, prognostic factors, and phenotype-genotype correlations...
September 3, 2018: Human Mutation
Irina Zaharieva, Anna Sarkozy, Pinki Munot, Adnan Manzur, Gina O'Grady, John Rendu, Eduardo Malfatti, Helge Amthor, Laurent Servais, J Andoni Urtizberea, Osorio Abath Neto, Edmar Zanoteli, Sandra Donkervoort, Juliet Taylor, Joanne Dixon, Gemma Poke, A Reghan Foley, Chris Holmes, Glyn Williams, Muriel Holder, Sabrina Yum, Livija Medne, Susana Quijano-Roy, Norma B Romero, Julien Fauré, Lucy Feng, Laila Bastaki, Mark R Davis, Rahul Phadke, Caroline A Sewry, Carsten G Bönnemann, Heinz Jungbluth, Christoph Bachmann, Susan Treves, Francesco Muntoni
STAC3 is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A Malignant Hyperthermia (MH) -like reaction had occurred in several patients...
August 31, 2018: Human Mutation
Grazia Nardella, Grazia Visci, Vito Guarnieri, Stefano Castellana, Tommaso Biagini, Luigi Bisceglia, Orazio Palumbo, Marina Trivisano, Carmela Vaira, Massimo Scerrati, Davide Debrasi, Vincenzo D'Angelo, Massimo Carella, Giuseppe Merla, Tommaso Mazza, Marco Castori, Leonardo D'Agruma, Carmela Fusco
Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance and variable expressivity. Three genes are associated with CCM KRIT1, CCM2 and PDCD10. This work is a retrospective single-centre molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients we found germline variants in either of the three genes in 80 (25...
August 30, 2018: Human Mutation
Candelaria Vergara, Samantha M Bomotti, Cristian Valencia, Barbara E K Klein, Kristine E Lee, Ronald Klein, Alison P Klein, Priya Duggal
Refractive errors, myopia and hyperopia are a common visual disorders greatly affecting older individuals. Refraction is determined by genetic factors but only a small percentages of its variation has been explained. We performed a genetic association analysis with three ocular phenotypes: refraction, axial length, and corneal curvature in 1,871 European-Americans from the Beaver Dam Eye Study. Individuals were genotyped on the Illumina exome array and imputed to the Haplotype Reference Consortium reference panel...
August 29, 2018: Human Mutation
Jorge L Granadillo, Wendy K Chung, Leah Hecht, Nicole Corsten-Janssen, Daniel Wegner, Sebastiaan W A Nij Bijvank, Tomi L Toler, Daniel E Pineda-Alvarez, Ganka Douglas, Joshua J Murphy, Joshua Shimony, Marwan Shinawi
SMAD2 is a downstream effector in the TGF-β signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patient 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature and poor weight gain...
August 29, 2018: Human Mutation
Ritu Dixit, Chitra Narasimhan, Vijyalakshmi I Balekundri, Damyanti Agrawal, Ashok Kumar, Bhagyalaxmi Mohapatra
Transcription factor GATA4 is known to play crucial role during heart development, regulating expression of several other key cardiogenic factors. Various GATA4 mutations are reported in familial as well as sporadic cases of congenital heart defects (CHDs). To estimate the prevalence and pathogenic potential of GATA4 variants in our CHD cohort, we have screened 285 CHD cases along with 200 controls by Sanger sequencing and identified 9 genetic variants (c.23C>A; p.Ala8Asp, c.25G>A; p.Ala9Thr, c.223G>T; p...
August 27, 2018: Human Mutation
Stephan Lauxmann, Nienke E Verbeek, Yuanyuan Liu, Mariana Zaichuk, Stephan Müller, Johannes R Lemke, Marjan J A van Kempen, Holger Lerche, Ulrike B S Hedrich
Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p...
August 24, 2018: Human Mutation
Meng Wang, Keith M Callenberg, Raymond Dalgleish, Alexandre Fedtsov, Naomi K Fox, Peter J Freeman, Kevin B Jacobs, Piotr Kaleta, Andrew J McMurry, Andreas Prlić, Veena Rajaraman, Reece K Hart
The Human Genome Variation Society (HGVS) nomenclature guidelines encourage the accurate and standard description of DNA, RNA, and protein sequence variants in public variant databases and the scientific literature. Inconsistent application of the HGVS guidelines can lead to misinterpretation of variants in clinical settings. Reliable software tools are essential to ensure consistent application of the HGVS guidelines when reporting and interpreting variants. We present the hgvs Python package, a comprehensive tool for manipulating sequence variants according to the HGVS nomenclature guidelines...
August 20, 2018: Human Mutation
Niti Kumari, Aman Kumar, Babu Ram Thapa, Manish Modi, Arnab Pal, Rajendra Prasad
Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort...
August 18, 2018: Human Mutation
Rosella Tomanin, Litsa Karageorgos, Alessandra Zanetti, Moeenaldeen Al-Sayed, Mitch Bailey, Nicole Miller, Hitoshi Sakuraba, John J Hopwood
Maroteaux-Lamy syndrome (MPS VI) is an autosomal recessive lysosomal storage disorder caused by pathogenic ARSB gene variants, commonly diagnosed through clinical findings and deficiency of the arylsulfatase B (ASB) enzyme. Detection of ARSB pathogenic variants can independently confirm diagnosis and render genetic counseling possible. In this review, we collect and summarize 908 alleles (201 distinct variants, including 3 polymorphisms previously considered as disease-causing variants) from 478 individuals diagnosed with MPS VI, identified from literature and public databases...
August 17, 2018: Human Mutation
Abby M Hodges, Aron W Fenton, Larissa L Dougherty, Andrew C Overholt, Liskin Swint-Kruse
Human mutations often cause amino acid changes (variants) that can alter protein function or stability. Some variants fall at protein positions that experimentally exhibit "rheostatic" mutation outcomes (different amino acid substitutions lead to a range of functional outcomes). In ongoing studies of rheostat positions, we encountered the need to aggregate experimental results from multiple variants, to describe the overall roles of individual positions. Here, we present "RheoScale" which generates quantitative scores to discriminate rheostat positions from those with "toggle" (most substitutions abolish function) or "neutral" (most substitutions have wild-type function) outcomes...
August 17, 2018: Human Mutation
Brad A Davidson, Shahzeb Hassan, Eric Joshua Garcia, Nahid Tayebi, Ellen Sidransky
Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder...
August 10, 2018: Human Mutation
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