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Missense variants & pathogenicity prediction

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https://www.readbyqxmd.com/read/29444077/peculiar-combinations-of-individually-non-pathogenic-missense-mitochondrial-dna-variants-cause-low-penetrance-leber-s-hereditary-optic-neuropathy
#1
Leonardo Caporali, Luisa Iommarini, Chiara La Morgia, Anna Olivieri, Alessandro Achilli, Alessandra Maresca, Maria Lucia Valentino, Mariantonietta Capristo, Francesca Tagliavini, Valentina Del Dotto, Claudia Zanna, Rocco Liguori, Piero Barboni, Michele Carbonelli, Veronica Cocetta, Monica Montopoli, Andrea Martinuzzi, Giovanna Cenacchi, Giuseppe De Michele, Francesco Testa, Anna Nesti, Francesca Simonelli, Anna Maria Porcelli, Antonio Torroni, Valerio Carelli
We here report on the existence of Leber's hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband's fibroblasts into the cybrid cell model...
February 14, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29429572/mutations-in-the-baf-complex-subunit-dpf2-are-associated-with-coffin-siris-syndrome
#2
Georgia Vasileiou, Silvia Vergarajauregui, Sabine Endele, Bernt Popp, Christian Büttner, Arif B Ekici, Marion Gerard, Nuria C Bramswig, Beate Albrecht, Jill Clayton-Smith, Jenny Morton, Susan Tomkins, Karen Low, Astrid Weber, Maren Wenzel, Janine Altmüller, Yun Li, Bernd Wollnik, George Hoganson, Maria-Renée Plona, Megan T Cho, Christian T Thiel, Hermann-Josef Lüdecke, Tim M Strom, Eduardo Calpena, Andrew O M Wilkie, Dagmar Wieczorek, Felix B Engel, André Reis
Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2)...
February 5, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29401559/spectrum-of-mnx1-pathogenic-variants-and-associated-clinical-features-in-korean-patients-with-currarino-syndrome
#3
Seungjun Lee, Eun Jin Kim, Sung Im Cho, Hyunwoong Park, Soo Hyun Seo, Moon Woo Seong, Sung Sup Park, Sung Eun Jung, Seong Cheol Lee, Kwi Won Park, Hyun Young Kim
BACKGROUND: The major genetic cause of Currarino syndrome (CS), a congenital malformation syndrome typically characterized by sacral agenesis, anorectal malformation, and presence of a pre-sacral mass, is known to be pathogenic variants in motor neuron and pancreas homeobox 1 (MNX1), which exist in almost all familial cases and 30% of sporadic cases. Less commonly, a large deletion or a complex rearrangement involving the 7q36 region is associated with CS. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in the Korean patients with CS...
May 2018: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/29399970/analysis-of-dicer1-in-familial-and-sporadic-cases-of-transposition-of-the-great-arteries
#4
Nelly Sabbaghian, Maria C Digilio, Gillian M Blue, Timothée Revil, David S Winlaw, William D Foulkes
OBJECTIVE: We previously identified a pathogenic germline DICER1 variant in a child with transposition of the great arteries who was a member of a family with DICER1 syndrome. In view of a report linking Dicer1 knockout in murine cardiomyocytes to cardiac outflow defects, we investigated the involvement of DICER1 in transposition of the great arteries. DESIGN: We used Fluidigm access array followed by next generation sequencing to screen for variants in the coding exons, their exon/intron boundaries and the 3' untranslated region of DICER1 in patient DNA...
February 5, 2018: Congenital Heart Disease
https://www.readbyqxmd.com/read/29394989/assessment-of-the-clinical-relevance-of-brca2-missense-variants-by-functional-and-computational-approaches
#5
Lucia Guidugli, Hermela Shimelis, David L Masica, Vernon S Pankratz, Gary B Lipton, Namit Singh, Chunling Hu, Alvaro N A Monteiro, Noralane M Lindor, David E Goldgar, Rachel Karchin, Edwin S Iversen, Fergus J Couch
Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ≥99% probability of pathogenicity, and 73 had ≥95% probability of neutrality...
January 17, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29386252/tumour-risks-and-genotype-phenotype-correlations-associated-with-germline-variants-in-succinate-dehydrogenase-subunit-genes-sdhb-sdhc-and-sdhd
#6
Katrina A Andrews, David B Ascher, Douglas Eduardo Valente Pires, Daniel R Barnes, Lindsey Vialard, Ruth T Casey, Nicola Bradshaw, Julian Adlard, Simon Aylwin, Paul Brennan, Carole Brewer, Trevor Cole, Jackie A Cook, Rosemarie Davidson, Alan Donaldson, Alan Fryer, Lynn Greenhalgh, Shirley V Hodgson, Richard Irving, Fiona Lalloo, Michelle McConachie, Vivienne P M McConnell, Patrick J Morrison, Victoria Murday, Soo-Mi Park, Helen L Simpson, Katie Snape, Susan Stewart, Susan E Tomkins, Yvonne Wallis, Louise Izatt, David Goudie, Robert S Lindsay, Colin G Perry, Emma R Woodward, Antonis C Antoniou, Eamonn R Maher
BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma...
January 31, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29373175/a-novel-point-mutation-affecting-asn76-of-dystrophin-protein-leads-to-dystrophinopathy
#7
Katalin Koczok, Gabriella Merő, Gabriella P Szabó, László Madar, Éva Gombos, Éva Ajzner, János András Mótyán, Tibor Hortobágyi, István Balogh
Mutations in the DMD gene lead to Duchenne and Becker muscular dystrophy (DMD/BMD). Missense mutations are rare cause of DMD/BMD. A six-month-old male patient presented with mild generalized muscle weakness, hypotonia, and delayed motor development. Dystrophinopathy was suspected because of highly elevated serum creatine kinase level (1497 U/L) and tiered DMD gene analysis was performed. Multiplex ligation-dependent probe amplification (MLPA) assay showed deletion of exon 4, which could not be confirmed by another method...
December 7, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29368626/brip1-loss-of-function-mutations-confer-high-risk-for-familial-ovarian-cancer-but-not-familial-breast-cancer
#8
Nana Weber-Lassalle, Jan Hauke, Juliane Ramser, Lisa Richters, Eva Groß, Britta Blümcke, Andrea Gehrig, Anne-Karin Kahlert, Clemens R Müller, Karl Hackmann, Ellen Honisch, Konstantin Weber-Lassalle, Dieter Niederacher, Julika Borde, Holger Thiele, Corinna Ernst, Janine Altmüller, Guido Neidhardt, Peter Nürnberg, Kristina Klaschik, Christopher Schroeder, Konrad Platzer, Alexander E Volk, Shan Wang-Gohrke, Walter Just, Bernd Auber, Christian Kubisch, Gunnar Schmidt, Judit Horvath, Barbara Wappenschmidt, Christoph Engel, Norbert Arnold, Bernd Dworniczak, Kerstin Rhiem, Alfons Meindl, Rita K Schmutzler, Eric Hahnen
BACKGROUND: Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. METHODS: To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants...
January 24, 2018: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29366874/novel-dcc-variants-in-congenital-mirror-movements-and-evaluation-of-disease-associated-missense-variants
#9
Tatjana Bierhals, Georg Christoph Korenke, Martina Baethmann, Laura López Marín, Martin Staudt, Kerstin Kutsche
Congenital mirror movements (CMM) are involuntary movements of one side of the body that mirror intentional movements of the other side. Heterozygous missense, frameshift and nonsense variants and small intragenic deletions in DCC cause CMM, isolated agenesis of the corpus callosum (ACC) or both. We report here the clinical phenotype and natural history of ten individuals with CMM carrying five different monoallelic DCC variants, including the missense variant p.(Trp273Arg), two duplications, one deletion and one deletion-insertion; all are novel and absent from databases...
January 20, 2018: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29361909/three-dimensional-spatial-analysis-of-missense-variants-in-rtel1-identifies-pathogenic-variants-in-patients-with-familial-interstitial-pneumonia
#10
R Michael Sivley, Jonathan H Sheehan, Jonathan A Kropski, Joy Cogan, Timothy S Blackwell, John A Phillips, William S Bush, Jens Meiler, John A Capra
BACKGROUND: Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. RESULTS: To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP)...
January 23, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29356034/rare-germline-mutations-in-african-american-men-diagnosed-with-early-onset-prostate-cancer
#11
Jennifer L Beebe-Dimmer, Kimberly A Zuhlke, Anna M Johnson, Daniel Liesman, Kathleen A Cooney
BACKGROUND: African Americans have both a higher incidence of prostate cancer and greater disease-specific mortality compared with non-Hispanic whites. Historically, the investigation of the contribution of rare genetic variants to prostate cancer in African American men has been hampered by low participation in large genetic studies, particularly those focused on early-onset and familial disease. METHODS: We sequenced 160 genes purported to be involved in carcinogenic pathways in germline DNA samples collected from 96 African American men diagnosed with early-onset prostate cancer (≤55 years at diagnosis)...
January 21, 2018: Prostate
https://www.readbyqxmd.com/read/29308445/utility-of-population-level-dna-sequence-data-in-the-diagnosis-of-hereditary-endocrine-disease
#12
Paul J Newey, Jonathan N Berg, Kaixin Zhou, Colin N A Palmer, Rajesh V Thakker
Context: Genetic testing is increasingly used for clinical diagnosis, although variant interpretation presents a major challenge because of high background rates of rare coding-region variation, which may contribute to inaccurate estimates of variant pathogenicity and disease penetrance. Objective: To use the Exome Aggregation Consortium (ExAC) data set to determine the background population frequencies of rare germline coding-region variants in genes associated with hereditary endocrine disease and to evaluate the clinical utility of these data...
December 1, 2017: Journal of the Endocrine Society
https://www.readbyqxmd.com/read/29304759/a-novel-compound-heterozygous-variant-identified-in-gldc-gene-in-a-chinese-family-with-non-ketotic-hyperglycinemia
#13
Yiming Lin, Zhenzhu Zheng, Wenjia Sun, Qingliu Fu
BACKGROUND: Non-ketotic hyperglycinemia (NKH) is a rare, devastating autosomal recessive disorder of glycine metabolism with a very poor prognosis. Currently, few studies have reported genetic profiling of Chinese NKH patients. This study aimed to identify the genetic mutations in a Chinese family with NKH. METHODS: A Chinese family of Han ethnicity, with three siblings with NKH was studied. Sanger sequencing and multiplex ligation-dependent probe amplification combined with SYBR green real-time quantitative PCR was used to identify potential mutations in the GLDC, AMT and GCSH genes...
January 5, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29290974/sodium-taurocholate-cotransporting-polypeptide-ntcp-deficiency-identification-of-a-novel-slc10a1-mutation-in-two-unrelated-infants-presenting-with-neonatal-indirect-hyperbilirubinemia-and-remarkable-hypercholanemia
#14
Jian-Wu Qiu, Mei Deng, Ying Cheng, Raza-Muhammad Atif, Wei-Xia Lin, Li Guo, Hua Li, Yuan-Zong Song
Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29260090/a-recurrent-non-penetrant-sequence-variant-p-arg266cys-in-growth-differentiation-factor-3-gdf3-in-a-female-with-unilateral-anophthalmia-and-skeletal-anomalies
#15
Tanya Bardakjian, Max Krall, Di Wu, Richard Lao, Paul Ling-Fung Tang, Eunice Wan, Sarina Kopinsky, Adele Schneider, Pui-Yan Kwok, Anne Slavotinek
Purpose: The genetic causes of anophthalmia, microphthalmia and coloboma remain poorly understood. Missense mutations in Growth/Differentiation Factor 3 (GDF3) gene have previously been reported in patients with microphthalmia, iridial and retinal colobomas, Klippel-Feil anomaly with vertebral fusion, scoliosis, rudimentary 12th ribs and an anomalous right temporal bone. We used whole exome sequencing with a trio approach to study a female with unilateral anophthalmia, kyphoscoliosis and additional skeletal anomalies...
September 2017: American Journal of Ophthalmology Case Reports
https://www.readbyqxmd.com/read/29231860/predicting-the-functional-impact-of-cdh1-missense-mutations-in-hereditary-diffuse-gastric-cancer
#16
REVIEW
Soraia Melo, Joana Figueiredo, Maria Sofia Fernandes, Margarida Gonçalves, Eurico Morais-de-Sá, João Miguel Sanches, Raquel Seruca
The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (CDH1) are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases CDH1 alterations result in the complete loss of E-cadherin associated with a well-established clinical impact, in about 20% of cases the mutations are of the missense type. The latter are of particular concern in terms of genetic counselling and clinical management, as the effect of the sequence variants in E-cadherin function is not predictable...
December 12, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29224747/next-generation-sequencing-identifies-three-novel-missense-variants-in-ildr1-and-myo6-genes-in-an-iranian-family-with-hearing-loss-with-review-of-the-literature
#17
Farah Talebi, Farideh Ghanbari Mardasi, Javad Mohammadi Asl, Masoomeh Sayahi
OBJECTIVES: Hearing impairment is the most common sensorineural disorder and is genetically heterogeneous. Identification of the pathogenic mutations underlying hearing impairment is difficult, since causative mutations in 127 different genes have so far been reported. METHODS: In this study, we performed Next-generation sequencing (NGS) in 2 individuals from a consanguineous family with hearing loss. RESULTS: Three novel mutations in known deafness genes were identified in the family; MYO6-p...
December 2017: International Journal of Pediatric Otorhinolaryngology
https://www.readbyqxmd.com/read/29224215/deleterious-variants-in-dchs1-are-prevalent-in-sporadic-cases-of-mitral-valve-prolapse
#18
Alisson Clemenceau, Jean-Christophe Bérubé, Paméla Bélanger, Nathalie Gaudreault, Maxime Lamontagne, Oumhani Toubal, Marie-Annick Clavel, Romain Capoulade, Patrick Mathieu, Philippe Pibarot, Yohan Bosse
BACKGROUND: A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. METHODS: DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico...
December 10, 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29208948/a-novel-mutation-in-slc1a3-causes-episodic-ataxia
#19
Kazuhiro Iwama, Aya Iwata, Masaaki Shiina, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Kazuhiro Ogata, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto
Episodic ataxias (EAs) are rare channelopathies characterized by recurrent ataxia and vertigo, having eight subtypes. Mutated genes were found in four of these eight subtypes (EA1, EA2, EA5, and EA6). To date, only four missense mutations in the Solute Carrier Family 1 Member 3 gene (SLC1A3) have been reported to cause EA6. SLC1A3 encodes excitatory amino-acid transporter 1, which is a trimeric transmembrane protein responsible for glutamate transport in the synaptic cleft. In this study, we found a novel missense mutation, c...
December 5, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29197658/utilizing-the-genome-aggregation-database-computational-pathogenicity-prediction-tools-and-patch-clamp-heterologous-expression-studies-to-demote-previously-published-type-1-long-qt-syndrome-mutations-from-pathogenic-to-benign
#20
Daniel J Clemens, Anne R Lentino, Jamie D Kapplinger, Dan Ye, Wei Zhou, David J Tester, Michael J Ackerman
BACKGROUND: Mutations in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). It has been suggested that ∼10-20% of rare LQTS case-derived variants in the literature may have been published erroneously as LQT1-causative mutations and may be "false positives." OBJECTIVE: To determine which previously published KCNQ1 case variants are likely false positives. METHODS: A list of all published, case-derived KCNQ1 missense variants (MVs) was compiled...
November 29, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
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