Daffodil Canson, Dylan Glubb, Amanda B Spurdle
No abstract text is available yet for this article.
December 2022: Human Mutation
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
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
Josine M de Winter, Karlijn Bouman, Joshua Strom, Mei Methawasin, Jan D 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 sixty-five evaluated patients, 12% presented with LV dilatation, 29% with LVEF<50%, 8% with atrial fibrillation, 9% with ventricular tachycardia and 20% with repolarization abnormalities...
November 6, 2022: Human Mutation
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
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...
November 1, 2022: Human Mutation
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
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
Vincent C T Hanlon, Peter M Lansdorp, Victor Guryev
Polymorphic inversions are ubiquitous in humans and they have been linked to both adaptation and disease. Following their discovery in Drosophila more than a century ago, inversions have proved to be more elusive than other structural variants. A wide variety of methods for the detection and genotyping of inversions have recently been developed: multiple techniques based on selective amplification by PCR, short- and long-read sequencing approaches, principal component analysis of small variant haplotypes, template strand sequencing, optical mapping, and various genome assembly methods...
November 2022: Human Mutation
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 API, such as MyVariant...
October 27, 2022: Human Mutation
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 1,210 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...
October 25, 2022: Human Mutation
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 machine learning approach, comprehensive assessment of variant effect on different splicing motifs...
October 23, 2022: Human Mutation
Manuela Lanzafame, Tiziana Nardo, Roberta Ricotti, Chiara Pantaleoni, Stefano D'Arrigo, Franco Stanzial, Francesco Benedicenti, Mary A Thomas, Miria Stefanini, Donata Orioli, Elena Botta
Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. The photosensitive form of TTD (PS-TTD) is most commonly caused by mutations in the ERCC2/XPD gene encoding a subunit of the transcription/DNA repair complex TFIIH. Here we report novel ERCC2/XPD mutations affecting proper protein folding, that generate thermo-labile forms of XPD associated with thermo-sensitive phenotypes characterized by reversible aggravation of TTD clinical signs during episodes of fever...
October 19, 2022: Human Mutation
Aiysha Abid, Ali Raza, Tahir Aziz, Shagufta Khaliq
The primary hyperoxalurias (PH) are a group of rare heterogeneous disorders characterized by deficiencies in glyoxylate metabolism. To date, three genes have been identified to cause three types of PH (I, II & III). The HOGA1 gene caused type III in around 10% of the PH cases. Disease-associated pathogenic variants have been reported from several populations and a comprehensive spectrum of these mutations and genotype-phenotype correlation has never been presented. In this study, we describe new cases of the HOGA1 gene pathogenic variants identified in our population...
October 19, 2022: Human Mutation
Rebekkah J Hitti-Malin, Claire-Marie Dhaenens, Daan M Panneman, Zelia Corradi, Mubeen Khan, Anneke I den Hollander, G Jane Farrar, Christian Gilissen, Alexander Hoischen, Maartje van de Vorst, Femke Bults, Erica G M Boonen, Patrick Saunders, Susanne Roosing, Frans P M Cremers
Macular diseases (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and non-genetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease to identify associated coding and non-coding variation, however many MD patients still remain genetically unexplained. We hypothesized that the missing heritability of MDs may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors...
October 19, 2022: Human Mutation
Rebecca L Margraf, Rachel Z Alexander, Makenzie L Fulmer, Christine E Miller, Elena Coupal, Rong Mao
The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma (MTC) onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature...
October 17, 2022: Human Mutation
Hannie C W Douben, Mark Nellist, Leontine van Unen, Peter Elfferich, Esmee Kasteleijn, Marianne Hoogeveen-Westerveld, Jesse Louwen, Monique van Veghel-Plandsoen, Walter de Valk, Jasper J Saris, Femke Hendriks, Esther Korpershoek, Lies H Hoefsloot, Margreethe van Vliet, Yolande van Bever, Ingrid van de Laar, Emmelien Aten, Augusta M A Lachmeijer, Walter Taal, Lisa van den Bersselaar, Juliette Schuurmans, Rianne Oostenbrink, Rick van Minkelen, Yvette van Ierland, Tjakko J van Ham
Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in NF1. Due to the size, complexity and high mutation rate at the NF1 locus, the identification of causative variants can be challenging. To obtain a molecular diagnosis in 15 individuals meeting diagnostic criteria for NF1, we performed transcriptome analysis (RNA-seq) on RNA obtained from cultured skin fibroblasts. In each case routine molecular DNA diagnostics had failed to identify a disease-causing variant in NF1. A pathogenic variant or abnormal mRNA splicing was identified in 13 cases: 6 deep intronic variants and 2 transposon insertions causing non-canonical splicing, 3 post-zygotic changes, one branchpoint mutation and, in one case, abnormal splicing for which the responsible DNA change remains to be identified...
October 17, 2022: Human Mutation
Yujia Lan, Wei Liu, Xiaobo Hou, Shuai Wang, Hao Wang, Menglan Deng, Guiyu Wang, Yanyan Ping, Xinxin Zhang
The clonal mutations in driver genes enable cells to gradually acquire growth advantage in tumor development. Therefore, revealing the functions of clonal driver gene mutations is important. Here, we proposed the method FCMP that considered evolutionary dependencies to analyze the functions of clonal driver gene mutations in a single patient. Applying our method to 5 cancer types from TCGA, we identified specific functions and common functions of clonal driver gene mutations. We found that the clonal driver gene mutations in the same patient played multiple functions...
October 11, 2022: Human Mutation
Kathryn P Burdon, Patricia Graham, Johanna Hadler, John D Hulleman, Francesca Pasutto, Erin A Boese, Jamie E Craig, John H Fingert, Alex W Hewitt, Owen M Siggs, Kristina Whisenhunt, Terri L Young, David A Mackey, Andrew Dubowsky, Emmanuelle Souzeau
The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines...
October 11, 2022: Human Mutation
Michael P Geaghan, William R Reay, Murray J Cairns
Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact non-coding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact. We intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predictions for miRNA binding site variants (MBSVs)...
October 11, 2022: Human Mutation
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