journal
https://read.qxmd.com/read/36448424/variant-effect-on-splicing-regulatory-elements-branchpoint-usage-and-pseudoexonization-strategies-to-enhance-bioinformatic-prediction-using-hereditary-cancer-genes-as-exemplars
#1
Daffodil Canson, Dylan Glubb, Amanda B Spurdle
No abstract text is available yet for this article.
December 2022: Human Mutation
https://read.qxmd.com/read/36335629/kbtbd13-is-a-novel-cardiomyopathy-gene
#2
JOURNAL ARTICLE
Josine M de Winter, Karlijn Bouman, Joshua Strom, Mei Methawasin, Jan D H Jongbloed, Wilma van der Roest, Jan van Wijngaarden, Janneke Timmermans, Robin Nijveldt, Frederik van den Heuvel, Erik-Jan Kamsteeg, Baziel G van Engelen, Ricardo Galli, Sylvia J P Bogaards, Reinier A Boon, Robbert J van der Pijl, Henk Granzier, Bobby Koeleman, Ahmad S Amin, Jolanda van der Velden, J Peter van Tintelen, Maarten P van den Berg, Karin Y van Spaendonck-Zwarts, Nicol C Voermans, Coen A C Ottenheijm
KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities...
December 2022: Human Mutation
https://read.qxmd.com/read/36317459/the-pathogenic-c-1171a-g-p-arg391gly-and-c-2359g-a-p-val787ile-abcc6-variants-display-incomplete-penetrance-causing-pseudoxanthoma-elasticum-in-a-subset-of-individuals
#3
JOURNAL ARTICLE
Flora Szeri, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere, Beatrix Molnar, Qiaoli Li, Sharon F Terry, Federica Boraldi, Jouni Uitto, Koen van de Wetering, Ludovic Martin, Daniela Quaglino, Olivier M Vanakker, Kalman Tory, Tamas Aranyi
ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort...
December 2022: Human Mutation
https://read.qxmd.com/read/36300680/variantalert-a-web-based-tool-to-notify-updates-in-genetic-variant-annotations
#4
JOURNAL ARTICLE
Rossano Atzeni, Matteo Massidda, Giorgio Fotia, Paolo Uva
The reinterpretation of variants based on updated annotations is part of the routine work of research laboratories: the more data is collected about a specific variant, the higher the probability to reinterpret its classification. To support this task, we developed VariantAlert, a web-based tool to help researchers and clinicians to be constantly informed about changes in variant annotations extracted from multiple sources. VariantAlert provides daily re-annotation of variants using external resources accessed through application programming interface, such as MyVariant...
December 2022: Human Mutation
https://read.qxmd.com/read/36284460/genetic-characterization-of-1210-japanese-pedigrees-with-inherited-retinal-diseases-by-whole-exome-sequencing
#5
JOURNAL ARTICLE
Akiko Suga, Kazutoshi Yoshitake, Naoko Minematsu, Kazushige Tsunoda, Kaoru Fujinami, Yozo Miyake, Kazuki Kuniyoshi, Takaaki Hayashi, Kei Mizobuchi, Shinji Ueno, Hiroko Terasaki, Taro Kominami, Nobuhisa Nao-I, Go Mawatari, Atsushi Mizota, Kei Shinoda, Mineo Kondo, Kumiko Kato, Tetsuju Sekiryu, Makoto Nakamura, Sentaro Kusuhara, Hiroyuki Yamamoto, Shuji Yamamoto, Kiyofumi Mochizuki, Hiroyuki Kondo, Itsuka Matsushita, Shuhei Kameya, Takeo Fukuchi, Tetsuhisa Hatase, Masayuki Horiguchi, Yoshiaki Shimada, Atsuhiro Tanikawa, Shuichi Yamamoto, Gen Miura, Nana Ito, Akira Murakami, Takuro Fujimaki, Yoshihiro Hotta, Koji Tanaka, Takeshi Iwata
Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees...
December 2022: Human Mutation
https://read.qxmd.com/read/36273432/spip-splicing-prediction-pipeline-a-machine-learning-tool-for-massive-detection-of-exonic-and-intronic-variant-effects-on-mrna-splicing
#6
JOURNAL ARTICLE
Raphaël Leman, Béatrice Parfait, Dominique Vidaud, Emmanuelle Girodon, Laurence Pacot, Gérald Le Gac, Chandran Ka, Claude Ferec, Yann Fichou, Céline Quesnelle, Camille Aucouturier, Etienne Muller, Dominique Vaur, Laurent Castera, Flavie Boulouard, Agathe Ricou, Hélène Tubeuf, Omar Soukarieh, Pascaline Gaildrat, Florence Riant, Marine Guillaud-Bataille, Sandrine M Caputo, Virginie Caux-Moncoutier, Nadia Boutry-Kryza, Françoise Bonnet-Dorion, Ines Schultz, Maria Rossing, Olivier Quenez, Louis Goldenberg, Valentin Harter, Michael T Parsons, Amanda B Spurdle, Thierry Frébourg, Alexandra Martins, Claude Houdayer, Sophie Krieger
Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5'/3' splice sites, branch sites, or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on a machine learning approach, a comprehensive assessment of the variant effect on different splicing motifs...
December 2022: Human Mutation
https://read.qxmd.com/read/36208099/biallelic-adamtsl4-variants-in-a-chinese-cohort-of-congenital-ectopia-lentis-implications-for-genotype-phenotype-relationships
#7
JOURNAL ARTICLE
Ze-Xu Chen, Wan-Nan Jia, Yang Sun, Tian-Hui Chen, Zhen-Nan Zhao, Li-Na Lan, Yan Liu, Ling-Hao Song, Yong-Xiang Jiang
ADAMTSL4 variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma. However, a genotype-phenotype correlation has not been established. Potentially pathogenic ADAMTSL4 variants were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing followed by multiple bioinformatics analyses. The genotype-phenotype correlation was assessed via a systematic review of ADAMTSL4 variants within our data and those from the literature...
December 2022: Human Mutation
https://read.qxmd.com/read/36150098/biallelic-loss-of-function-variants-in-exoc6b-are-associated-with-impaired-primary-ciliogenesis-and-cause-spondylo-epi-metaphyseal-dysplasia-with-joint-laxity-type-3
#8
REVIEW
Pelin Ozlem Simsek-Kiper, Prince Jacob, Priyanka Upadhyai, Zihni Ekim Taşkıran, Vishal S Guleria, Beren Karaosmanoglu, Gozde Imren, Rahsan Gocmen, Gandham S Bhavani, Neethukrishna Kausthubham, Hitesh Shah, Gulen Eda Utine, Koray Boduroglu, Katta M Girisha
Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c...
December 2022: Human Mutation
https://read.qxmd.com/read/36135717/biallelic-loss-of-function-mutations-in-septin4-c17orf47-encoding-a-conserved-annulus-protein-cause-thin-midpiece-spermatozoa-and-male-infertility-in-humans
#9
JOURNAL ARTICLE
Guanxiong Wang, Xiaoyu Zhu, Yang Gao, Mingrong Lv, Kuokuo Li, Dongdong Tang, Huan Wu, Chuan Xu, Hao Geng, Qunshan Shen, Xiaomin Zha, Zongliu Duan, Jingjing Zhang, Rong Hua, Fangbiao Tao, Ping Zhou, Zhaolian Wei, Yunxia Cao, Rui Guo, Xiaojin He
Asthenoteratozoospermia is the primary cause of infertility in humans. However, the genetic etiology remains largely unknown for those suffering from severe asthenoteratozoospermia caused by thin midpiece defects. In this study, we identified two biallelic loss-of-function variants of SEPTIN4 (previously SEPT4) (Patient 1: c.A721T, p.R241* and Patient 2: c.C205T, p.R69*) in two unrelated individuals from two consanguineous Chinese families. SEPT4 is a conserved annulus protein that is critical for male fertility and the structural integrity of the sperm midpiece in mice...
December 2022: Human Mutation
https://read.qxmd.com/read/36054329/de-novo-variant-calling-identifies-cancer-mutation-signatures-in-the-1000-genomes-project
#10
JOURNAL ARTICLE
Jeffrey K Ng, Pankaj Vats, Elyn Fritz-Waters, Stephanie Sarkar, Eleanor I Sams, Evin M Padhi, Zachary L Payne, Shawn Leonard, Marc A West, Chandler Prince, Lee Trani, Marshall Jansen, George Vacek, Mehrzad Samadi, Timothy T Harkins, Craig Pohl, Tychele N Turner
Detection of de novo variants (DNVs) is critical for studies of disease-related variation and mutation rates. To accelerate DNV calling, we developed a graphics processing units-based workflow. We applied our workflow to whole-genome sequencing data from three parent-child sequenced cohorts including the Simons Simplex Collection (SSC), Simons Foundation Powering Autism Research (SPARK), and the 1000 Genomes Project (1000G) that were sequenced using DNA from blood, saliva, and lymphoblastoid cell lines (LCLs), respectively...
December 2022: Human Mutation
https://read.qxmd.com/read/36054313/long-read-sequencing-and-expression-studies-of-ahdc1-deletions-in-xia-gibbs-syndrome-reveal-a-novel-genetic-regulatory-mechanism
#11
JOURNAL ARTICLE
Varuna Chander, Medhat Mahmoud, Jianhong Hu, Zain Dardas, Christopher M Grochowski, Moez Dawood, Michael M Khayat, He Li, Shoudong Li, Shalini Jhangiani, Viktoriya Korchina, Hua Shen, George Weissenberger, Qingchang Meng, Marie-Claude Gingras, Donna M Muzny, Harsha Doddapaneni, Jennifer E Posey, James R Lupski, Aniko Sabo, David R Murdock, Fritz J Sedlazeck, Richard A Gibbs
Xia-Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein-truncating mutations in the AT-Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity...
December 2022: Human Mutation
https://read.qxmd.com/read/36030551/biallelic-pathogenic-variants-in-cox11-are-associated-with-an-infantile-onset-mitochondrial-encephalopathy
#12
JOURNAL ARTICLE
Rocio Rius, Neal K Bennett, Kaustuv Bhattacharya, Lisa G Riley, Zafer Yüksel, Luke E Formosa, Alison G Compton, Russell C Dale, Mark J Cowley, Velimir Gayevskiy, Saeed M Al Tala, Abdulrahman A Almehery, Michael T Ryan, David R Thorburn, Ken Nakamura, John Christodoulou
Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular adenosine triphosphate (ATP) derived from respiration, and that ATP levels could be restored with coenzyme Q10 (CoQ10 ) supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis...
December 2022: Human Mutation
https://read.qxmd.com/read/35904126/de-novo-putative-loss-of-function-variants-in-taf4-are-associated-with-a-neuro-developmental-disorder
#13
JOURNAL ARTICLE
Beau D E Janssen, Marie-Jose H van den Boogaard, Klaske Lichtenbelt, Eleanor G Seaby, Karen Stals, Sian Ellard, Ruth Newbury-Ecob, Abhijit Dixit, Laura Roht, Sander Pajusalu, Katrin Õunap, Helen V Firth, Michael Buckley, Meredith Wilson, Tony Roscioli, Timothy Tidwell, Rong Mao, Sarah Ennis, Sjoerd J Holwerda, Koen van Gassen, Richard H van Jaarsveld
TATA-binding protein associated factor 4 (TAF4) is a subunit of the Transcription Factor IID (TFIID) complex, a central player in transcription initiation. Other members of this multimeric complex have been implicated previously as monogenic disease genes in human developmental disorders. TAF4 has not been described to date as a monogenic disease gene. We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD)...
December 2022: Human Mutation
https://read.qxmd.com/read/35904125/expanding-the-phenotypic-variability-of-morc2-gene-mutations-from-charcot-marie-tooth-disease-to-late-onset-pure-motor-neuropathy
#14
JOURNAL ARTICLE
Arnaud Jacquier, Shams Ribault, Michel Mendes, Nicolas Lacoste, Valérie Risson, Julien Carras, Philippe Latour, Aleksandra Nadaj-Pakleza, Tanya Stojkovic, Laurent Schaeffer
MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge...
December 2022: Human Mutation
https://read.qxmd.com/read/35842788/biallelic-nlrp7-variants-in-patients-with-recurrent-hydatidiform-mole-a-review-and-expert-consensus
#15
REVIEW
Rima Slim, Rosemary Fisher, Florian Milhavet, Reda Hemida, Samantha Rojas, Cécile Rittore, Rashmi Bagga, Monica Aguinaga, Isabelle Touitou
Hydatidiform mole (HM) is an abnormal human pregnancy characterized by excessive growth of placental trophoblasts and abnormal early embryonic development. Following a first such abnormal pregnancy, the risk for women of successive molar pregnancies significantly increases. To date variants in seven maternal-effect genes have been shown to cause recurrent HMs (RHM). NLRP7 is the major causative gene for RHM and codes for NOD-like receptor (NLR) family pyrin domain containing 7, which belongs to a family of proteins involved in inflammatory disorders...
December 2022: Human Mutation
https://read.qxmd.com/read/35842780/deep-intronic-nipbl-de-novo-mutations-and-differential-diagnoses-revealed-by-whole-genome-and-rna-sequencing-in-cornelia-de-lange-syndrome-patients
#16
JOURNAL ARTICLE
Juliette Coursimault, Kévin Cassinari, François Lecoquierre, Olivier Quenez, Sophie Coutant, Céline Derambure, Myriam Vezain, Nathalie Drouot, Gabriella Vera, Elise Schaefer, Anaïs Philippe, Bérénice Doray, Laëtitia Lambert, Jamal Ghoumid, Thomas Smol, Mélanie Rama, Marine Legendre, Didier Lacombe, Patricia Fergelot, Robert Olaso, Anne Boland, Jean-François Deleuze, Alice Goldenberg, Pascale Saugier-Veber, Gaël Nicolas
Cornelia de Lange syndrome (CdLS; MIM# 122470) is a rare developmental disorder. Pathogenic variants in 5 genes explain approximately 50% cases, leaving the other 50% unsolved. We performed whole genome sequencing (WGS) ± RNA sequencing (RNA-seq) in 5 unsolved trios fulfilling the following criteria: (i) clinical diagnosis of classic CdLS, (ii) negative gene panel sequencing from blood and saliva-isolated DNA, (iii) unaffected parents' DNA samples available and (iv) proband's blood-isolated RNA available...
December 2022: Human Mutation
https://read.qxmd.com/read/36349709/germline-selection-of-ptpn11-hgnc-9644-variants-make-a-major-contribution-to-both-noonan-syndrome-s-high-birth-rate-and-the-transmission-of-sporadic-cancer-variants-resulting-in-fetal-abnormality
#17
JOURNAL ARTICLE
Jordan Eboreime, Soo-Kyung Choi, Song-Ro Yoon, Anastasiia Sadybekov, Vsevolod Katritch, Peter Calabrese, Norman Arnheim
Some spontaneous germline gain-of-function mutations promote spermatogonial stem cell clonal expansion and disproportionate variant sperm production leading to unexpectedly high transmission rates for some human genetic conditions. To measure the frequency and spatial distribution of de novo mutations we divided three testes into 192 pieces each and used error-corrected deep-sequencing on each piece. We focused on PTPN11 (HGNC:9644) Exon 3 that contains 30 different PTPN11 Noonan syndrome mutation sites. We found 14 of these variants formed clusters among the testes; one testis had 11 different variant clusters...
November 9, 2022: Human Mutation
https://read.qxmd.com/read/36317469/comprehensive-analysis-of-the-prpf31-gene-in-retinitis-pigmentosa-patients-four-novel-alu-mediated-copy-number-variations-at-the-prpf31-locus
#18
JOURNAL ARTICLE
Zhixuan Chen, Jieqiong Chen, Min Gao, Yang Liu, Yidong Wu, Yafang Wang, Yuanyuan Gong, Suqin Yu, Wenjia Liu, Xiaoling Wan, Xiaodong Sun
Retinitis pigmentosa (RP) is a monogenic disease characterized by irreversible degeneration of the retina. PRPF31, the second most common causative gene of autosomal dominant RP, frequently harbors copy number variants (CNVs), but the underlying mechanism is unclear. In this study, we summarized the phenotypic and genotypic characteristics of 18 RP families (F01-F18) with variants in PRPF31. The prevalence of PRPF31 variants in our cohort of Chinese RP families was 1.7% (18/1024). Seventeen different variants in PRPF31 were detected, including eight novel variants...
November 1, 2022: Human Mutation
https://read.qxmd.com/read/36317458/a-recurrent-single-exon-deletion-in-tbckmight-be-under-recognizedin-patients-with-infantile-hypotonia-and-psychomotor-delay
#19
JOURNAL ARTICLE
Hongzheng Dai, Wenmiao Zhu, Bo Yuan, Nicole Walley, Kelly Schoch, Yong-Hui Jiang, John A Phillips, Melissa S Jones, Pengfei Liu, David R Murdock, Lindsay C Burrage, Brendan Lee, Jill A Rosenfeld, Rui Xiao
Advanced bioinformatics algorithms allow detection of multiple-exon copy-number variations (CNVs) from exome sequencing (ES) data, whiledetection of single-exon CNVsremainschallenging.A retrospective review of Baylor Genetics' clinical ES patient cohort identified four individualswith homozygous single-exon deletions of TBCK(exon23, NM_001163435.2), a gene associated with an autosomal recessive neurodevelopmental phenotype. To evaluate the prevalence of this deletion and its contribution to disease, we retrospectively analyzedsingle nucleotide polymorphism (SNP) array data for 8194 individuals undergoing ES, followed by PCR confirmation and RT-PCR on individuals carrying homozygous or heterozygous exon23 TBCK deletions...
November 1, 2022: Human Mutation
https://read.qxmd.com/read/36317447/new-clinical-and-molecular-evidence-linking-mutations-in-arsg-to-usher-syndrome-type-iv
#20
Virginie G Peter, Mathieu Quinodoz, Silvia Sadio, Sebastian Held, Márcia Rodrigues, Marta Soares, Ana Berta Sousa, Luisa Coutinho Santos, Markus Damme, Carlo Rivolta
The correct figure should show a white area in the centre of the black field (indicating preserved vision), which is not the case in the published version of the article, and it is therefore incorrect from a scientific standpoint. The correct figure should be as follows This article is protected by copyright. All rights reserved.
November 1, 2022: Human Mutation
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