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Variant effect on splicing regulatory elements, branchpoint usage, and pseudoexonization: Strategies to enhance bioinformatic prediction using hereditary cancer genes as exemplars Hum. Mutat. (IF 3.9) Pub Date : 2022-11-30 Daffodil Canson, Dylan Glubb, Amanda B. Spurdle
Human Mutation, 41, 1705–1721 (2020). https://doi.org/10.1002/humu.24074 Dylan Glubb co-supervised first author Daffodil Canson through an Honorary appointment at the University of Queensland and he should be recognized as affiliated to below affiliation [2] in the original paper. 2Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
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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 Hum. Mutat. (IF 3.9) Pub Date : 2022-11-09 Jordan Eboreime, Soo-Kyung Choi, Song-Ro Yoon, Anastasiia Sadybekov, Vsevolod Katritch, Peter Calabrese, Norman Arnheim
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KBTBD13 is a novel cardiomyopathy gene Hum. Mutat. (IF 3.9) Pub Date : 2022-11-06 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
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
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New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV Hum. Mutat. (IF 3.9) Pub Date : 2022-11-01 Virginie G. Peter, Mathieu Quinodoz, Silvia Sadio, Sebastian Held, Márcia Rodrigues, Marta Soares, Ana Berta Sousa, Luisa Coutinho Santos, Markus Damme, Carlo Rivolta
Human Mutation, 42, 261–271 (2021) https://doi.org/10.1002/humu.24150 The correct figure should show a white area in the center 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: Figure 1 Figure 1 Open in figure viewerPowerPoint The publisher
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Comprehensive analysis of the PRPF31 gene in retinitis pigmentosa patients: Four novel Alu-mediated copy number variations at the PRPF31 locus Hum. Mutat. (IF 3.9) Pub Date : 2022-11-01 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 variations (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
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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 Hum. Mutat. (IF 3.9) Pub Date : 2022-11-01 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
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A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay Hum. Mutat. (IF 3.9) Pub Date : 2022-11-01 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
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VariantAlert: A web-based tool to notify updates in genetic variant annotations Hum. Mutat. (IF 3.9) Pub Date : 2022-10-27 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
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Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing Hum. Mutat. (IF 3.9) Pub Date : 2022-10-25 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
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
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SPiP: Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing Hum. Mutat. (IF 3.9) Pub Date : 2022-10-23 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,
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
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HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association Hum. Mutat. (IF 3.9) Pub Date : 2022-10-19 Aiysha Abid, Ali Raza, Tahir Aziz, Shagufta Khaliq
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, and 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
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TFIIH stabilization recovers the DNA repair and transcription dysfunctions in thermo-sensitive trichothiodystrophy Hum. Mutat. (IF 3.9) Pub Date : 2022-10-19 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
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Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases Hum. Mutat. (IF 3.9) Pub Date : 2022-10-19 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 degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic 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
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Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database Hum. Mutat. (IF 3.9) Pub Date : 2022-10-17 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
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High-yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing Hum. Mutat. (IF 3.9) Pub Date : 2022-10-17 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
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,
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Front Cover, Volume 43, Issue 11 Hum. Mutat. (IF 3.9) Pub Date : 2022-10-11 Stuart A. Scott, Kai Wang, Nancy B. Spinner
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Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel Hum. Mutat. (IF 3.9) Pub Date : 2022-10-11 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)
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MicroRNA binding site variation is enriched in psychiatric disorders Hum. Mutat. (IF 3.9) Pub Date : 2022-10-11 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 noncoding 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
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Revealing the functions of clonal driver gene mutations in patients based on evolutionary dependencies Hum. Mutat. (IF 3.9) Pub Date : 2022-10-11 Yujia Lan, Wei Liu, Xiaobo Hou, Shuai Wang, Hao Wang, Menglan Deng, Guiyu Wang, Yanyan Ping, Xinxin Zhang
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Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype–phenotype relationships Hum. Mutat. (IF 3.9) Pub Date : 2022-10-08 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
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Exome sequencing unravels genetic variants associated with chronic kidney disease in Saudi Arabian patients Hum. Mutat. (IF 3.9) Pub Date : 2022-09-30 Mohamed H. Al-Hamed, Maged H. Hussein, Yaser Shah, Hamad Al-Mojalli, Essam Alsabban, Turki Alshareef, Ali Altayyar, Samir Elshouny, Wafaa Ali, Mai Abduljabbar, Afaf AlOtaibi, Amal AlShammasi, Rana Akili, Mohamed Abouelhoda, John A. Sayer, Majed J. Dasouki, Faiqa Imtiaz
The use of genetic testing within nephrology is increasing and its diagnostic yield depends on the methods utilized, patient selection criteria, and population characteristics. We performed exome sequencing (ES) analysis on 102 chronic kidney disease (CKD) patients with likely genetic kidney disease. Patients had diverse CKD subtypes with/without consanguinity, positive family history, and possible
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Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A Hum. Mutat. (IF 3.9) Pub Date : 2022-09-24 Elena V. Pavlova, Dorit Lev, Marina Michelson, Keren Yosovich, Hila Gur Michaeli, Nicholas A. Bright, Paul T. Manna, Veronica Kane Dickson, Karen L. Tylee, Heather J. Church, J. Paul Luzio, Timothy M. Cox
A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS, and CORVET. Whole exome sequencing identified a novel VPS33A mutation in a patient suffering from a variant form of mucopolysaccharidosis. Electron and confocal microscopy
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ENPP1 deficiency: A clinical update on the relevance of individual variants using a locus-specific patient database Hum. Mutat. (IF 3.9) Pub Date : 2022-09-23 Stephanie A. Mercurio, Lauren M. Chunn, Gus Khursigara, Catherine Nester, Kathleen Wray, Ulrike Botschen, Mark J. Kiel, Frank Rutsch, Carlos R. Ferreira
Loss-of-function variants in the ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) cause ENPP1 Deficiency, a rare disorder characterized by pathological calcification, neointimal proliferation, and impaired bone mineralization. The consequence of ENPP1 Deficiency is a broad range of age dependent symptoms and morbidities including cardiovascular complications and 50% mortality
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Biallelic loss-of-function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo-epi-metaphyseal dysplasia with joint laxity type 3 Hum. Mutat. (IF 3.9) Pub Date : 2022-09-23 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
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Rare surfactant-related variants in familial and sporadic pulmonary fibrosis Hum. Mutat. (IF 3.9) Pub Date : 2022-09-22 Rachel M. Sutton, Humberto Trejo Bittar, Daniel I. Sullivan, Agustin Gil Silva, Harinath Bahudhanapati, Anishka H. Parikh, Yingze Zhang, Kevin Gibson, John F. McDyer, Daniel J. Kass, Jonathan K. Alder
The role of constitutional genetic defects in idiopathic pulmonary fibrosis (IPF) is increasingly appreciated. Monogenic disorders associated with IPF affect two pathways: telomere maintenance, accounting for approximately 10% of all patients with IPF, and surfactant biology, responsible for 1%–3% of cases and often co-occurring with lung cancer. We examined the prevalence of rare variants in five
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Biallelic loss-of-function mutations in SEPTIN4 (C17ORF47), encoding a conserved annulus protein, cause thin midpiece spermatozoa and male infertility in humans Hum. Mutat. (IF 3.9) Pub Date : 2022-09-22 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
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Destabilization of mutated human PUS3 protein causes intellectual disability Hum. Mutat. (IF 3.9) Pub Date : 2022-09-20 Ting-Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec-Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca-Niewczas, Magdalena Dziembowska, Rafał Ploski, Sebastian Glatt
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Mutations in the TBX15-ADAMTS2 pathway associate with a novel soft palate dysplasia Hum. Mutat. (IF 3.9) Pub Date : 2022-09-19 Yuying Zhang, Jian Li, Yaoting Ji, Yibin Cheng, Xiazhou Fu
We reported de novo variants in specific exons of the TBX15 and ADAMTS2 genes in a hitherto undescribed class of patients with unique craniofacial developmental defects. The nine unrelated patients represent unilateral soft palate hypoplasia, lost part of the sphenoid bone in the pterygoid process, but the uvula developed completely. Interestingly, these clinical features are contrary to the palate's
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Mutation update for the ACTN2 gene Hum. Mutat. (IF 3.9) Pub Date : 2022-09-18 Johanna Ranta-aho, Montse Olive, Marie Vandroux, Giorgia Roticiani, Cristina Dominguez, Mridul Johari, Annalaura Torella, Johann Böhm, Janina Turon, Vincenzo Nigro, Peter Hackman, Jocelyn Laporte, Bjarne Udd, Marco Savarese
ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle. The protein, located in the sarcomere Z-disk, functions as a link between the anti-parallel actin filaments. This important structural protein also binds N-terminal titins, and thus contributes to sarcomere stability. Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal
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Functional characterization of a novel TP53RK mutation identified in a family with Galloway–Mowat syndrome Hum. Mutat. (IF 3.9) Pub Date : 2022-09-18 Ernestine Treimer, Tugba Kalayci, Sven Schumann, Ilknur Suer, Sara Greco, Denny Schanze, Michael J. Schmeisser, Susanne J. Kühl, Martin Zenker
Galloway–Mowat syndrome (GAMOS) is a very rare condition characterized by early-onset nephrotic syndrome and microcephaly with variable neurologic features. While considerable genetic heterogeneity of GAMOS has been identified, the majority of cases are caused by pathogenic variants in genes encoding the four components of the Kinase, endopeptidase, and other proteins of small size (KEOPS) complex
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Next-generation sequencing errors due to genetic variation in WRAP53 encoding TCAB1 on chromosome 17 Hum. Mutat. (IF 3.9) Pub Date : 2022-09-18 Sharon A. Savage, Kristine Jones, Kedest Teshome, Adriana Lori, Lisa J. McReynolds, Marena R. Niewisch
Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate
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Human Mutation special issue on innovations in genomic diagnostics Hum. Mutat. (IF 3.9) Pub Date : 2022-09-18 Stuart A. Scott, Kai Wang, Nancy B. Spinner
This special issue of Human Mutation focuses on Innovations in Genomic Diagnostics. The increasing interest in genomic medicine, and the growing possibilities for treatment and management of genetic disease, make complete and accurate diagnosis mission critical. This issue describes leading-edge technologies with emerging utility for genomic diagnostics. Genomic testing has dramatically evolved as
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Next-generation phenotyping contributing to the identification of a 4.7 kb deletion in KANSL1 causing Koolen-de Vries syndrome Hum. Mutat. (IF 3.9) Pub Date : 2022-09-14 Fabian Brand, Aswinkumar Vijayananth, Tzung-Chien Hsieh, Axel Schmidt, Sophia Peters, Elisabeth Mangold, Kirsten Cremer, Tim Bender, Sugirthan Sivalingam, Hela Hundertmark, Alexej Knaus, Hartmut Engels, Peter M. Krawitz, Claudia Perne
Next-generation phenotyping (NGP) is an application of advanced methods of computer vision on medical imaging data such as portrait photos of individuals with rare disorders. NGP on portraits results in gestalt scores that can be used for the selection of appropriate genetic tests, and for the interpretation of the molecular data. Here, we report on an exceptional case of a young girl that was presented
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Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions Hum. Mutat. (IF 3.9) Pub Date : 2022-09-12 Aimee L. Davidson, Olga Kondrashova, Conrad Leonard, Scott Wood, Emma Tudini, Georgina E. Hollway, John V. Pearson, Felicity Newell, Amanda B. Spurdle, Nicola Waddell
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Rapid genome sequencing for pediatrics Hum. Mutat. (IF 3.9) Pub Date : 2022-09-10 Jana Jezkova, Sophie Shaw, Nicola V. Taverner, Hywel J. Williams
The advancements made in next-generation sequencing (NGS) technology over the past two decades have transformed our understanding of genetic variation in humans and had a profound impact on our ability to diagnose patients with rare genetic diseases. In this review, we discuss the recently developed application of rapid NGS techniques, used to diagnose pediatric patients with suspected rare diseases
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Long-read sequencing for molecular diagnostics in constitutional genetic disorders Hum. Mutat. (IF 3.9) Pub Date : 2022-09-10 Laura K. Conlin, Erfan Aref-Eshghi, Deborah A. McEldrew, Minjie Luo, Ramakrishnan Rajagopalan
Long-read sequencing (LRS) has been around for more than a decade, but widespread adoption of the technology has been slow due to the perceived high error rates and high sequencing cost. This is changing due to the recent advancements to produce highly accurate sequences and the reducing costs. LRS promises significant improvement over short read sequencing in four major areas: (1) better detection
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Long-read HiFi sequencing of NUDT15: Phased full-gene haplotyping and pharmacogenomic allele discovery Hum. Mutat. (IF 3.9) Pub Date : 2022-09-04 Erick R. Scott, Yao Yang, Mariana R. Botton, Yoshinori Seki, Keito Hoshitsuki, John Harting, Primo Baybayan, Neal Cody, Paola Nicoletti, Takaya Moriyama, Shreyasee Chakraborty, Jun J. Yang, Lisa Edelmann, Eric E. Schadt, Jonas Korlach, Stuart A. Scott
To determine the phase of NUDT15 sequence variants for more comprehensive star (*) allele diplotyping, we developed a novel long-read single-molecule real-time HiFi amplicon sequencing method. A 10.5 kb NUDT15 amplicon assay was validated using reference material positive controls and additional samples for specimen type and blinded accuracy assessment. Triplicate NUDT15 HiFi sequencing of two reference
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Front Cover, Volume 43, Issue 10 Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 Sheng-Jia Lin, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang, Yves Lacassie, Jill A. Rosenfeld, Saadullah Khan, Cassidy Petree, Tayyiba A. Ali, Nazif Muhammad, Sher A. Khan, Noor Muhammad, Pengfei Liu, Marie-Louise Haymon, Franz Rüschendorf, Il-Keun Kong, Linda Schnapp, Natasha Shur, Lynn Chorich, Lawrence Layman, Thomas Haaf, Ehsan Pourkarimi, Hyung-Goo Kim, Gaurav K. Varshney
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de novo variant calling identifies cancer mutation signatures in the 1000 Genomes Project Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 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
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A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 Abhijit Rath, Alexander A. Radecki, Kaussar Rahman, Rachel B. Gilmore, Jonathan R. Hudson, Matthew Cenci, Sean V. Tavtigian, James P. Grady, Christopher D. Heinen
Functional assays provide important evidence for classifying the disease significance of germline variants in DNA mismatch repair genes. Numerous laboratories, including our own, have developed functional assays to study mismatch repair gene variants. However, previous assays are limited due to the model system employed, the manner of gene expression, or the environment in which function is assessed
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CIC missense variants contribute to susceptibility for spina bifida Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 Xiao Han, Xuanye Cao, Vanessa Aguiar-Pulido, Wei Yang, Menuka Karki, Paula Andrea Pimienta Ramirez, Robert M. Cabrera, Ying Linda Lin, Bogdan J. Wlodarczyk, Gary M. Shaw, M. Elizabeth Ross, Cuilian Zhang, Richard H. Finnell, Yunping Lei
Neural tube defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia
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Cancer-causing MAP2K1 mutation in a mosaic patient with cardio-facio-cutaneous syndrome and immunodeficiency Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 Victorya Zakharova, Elena Raykina, Irina Mersiyanova, Ekaterina Deordieva, Dmitry Pershin, Victorya Vedmedskia, Yulia Rodina, Natalia Kuzmenko, Michael Maschan, Anna Shcherbina
RASopathies are disorders caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. These syndromes share features of developmental delay, facial dysmorphisms, and defects in various organs, as well as cancer predisposition. Somatic mutations of the same pathway are one of the primary causes of cancer. It is thought that germline cancer-causing
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Evaluation of a whole-exome sequencing pipeline and benchmarking of causal germline variant prioritizers Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 Eva Tosco-Herrera, Adrián Muñoz-Barrera, David Jáspez, Luis A. Rubio-Rodríguez, Alejandro Mendoza-Alvarez, Hector Rodriguez-Perez, Jonathan Jou, Antonio Iñigo-Campos, Almudena Corrales, Laura Ciuffreda, Francisco Martinez-Bugallo, Carol Prieto-Morin, Víctor García-Olivares, Rafaela González-Montelongo, Jose Miguel Lorenzo-Salazar, Itahisa Marcelino-Rodriguez, Carlos Flores
Most causal variants of Mendelian diseases are exonic. Whole-exome sequencing (WES) has become the diagnostic gold standard, but causative variant prioritization constitutes a bottleneck. Here we assessed an in-house sample-to-sequence pipeline and benchmarked free prioritization tools for germline causal variants from WES data. WES of 61 unselected patients with a known genetic disease cause was obtained
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Long read sequencing and expression studies of AHDC1 deletions in Xia-Gibbs syndrome reveal a novel genetic regulatory mechanism Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 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
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Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms Hum. Mutat. (IF 3.9) Pub Date : 2022-09-02 Marlies Colman, Robin Vroman, Tibbe Dhooge, Zoë Malfait, Sofie Symoens, Biruté Burnyté, Sheela Nampoothiri, Ariana Kariminejad, Fransiska Malfait, Delfien Syx
The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue diseases. The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross-linking; or the peptidyl-prolyl cis-trans isomerase family FK506-binding protein 22 kDa (FKBP22 encoded by FKBP14), a molecular chaperone of types III, IV,
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A survey of current methods to detect and genotype inversions Hum. Mutat. (IF 3.9) Pub Date : 2022-09-01 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
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Phasing of de novo mutations using a scaled-up multiple amplicon long-read sequencing approach Hum. Mutat. (IF 3.9) Pub Date : 2022-09-01 Giles S. Holt, Lois E. Batty, Bilal K. S. Alobaidi, Hannah E. Smith, Manon S. Oud, Liliana Ramos, Miguel J. Xavier, Joris A. Veltman
De novo mutations (DNMs) play an important role in severe genetic disorders that reduce fitness. To better understand their role in disease, it is important to determine the parent-of-origin and timing of mutational events that give rise to these mutations, especially in sex-specific developmental disorders such as male infertility. However, currently available short-read sequencing approaches are
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Mosaicism in tuberous sclerosis complex: Lowering the threshold for clinical reporting Hum. Mutat. (IF 3.9) Pub Date : 2022-08-28 Zimeng Ye, Sufang Lin, Xia Zhao, Mark F. Bennett, Natasha J. Brown, Mathew Wallis, Xinyi Gao, Li Sun, Jiarui Wu, Ravikiran Vedururu, Tom Witkowski, Fiona Gardiner, Chloe Stutterd, Jing Duan, Saul A. Mullen, George McGillivray, Simon Bodek, Giulia Valente, Matthew Reagan, Yi Yao, Lin Li, Li Chen, Amber Boys, Thiuni N. Adikari, Dezhi Cao, Zhanqi Hu, Victoria Beshay, Victor W. Zhang, Samuel F. Berkovic
Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%–15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine
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Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy Hum. Mutat. (IF 3.9) Pub Date : 2022-08-28 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
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AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders Hum. Mutat. (IF 3.9) Pub Date : 2022-08-23 Johann Kaspar Lieberwirth, Benjamin Büttner, Chiara Klöckner, Konrad Platzer, Bernt Popp, Rami Abou Jamra
Routine exome sequencing (ES) in individuals with neurodevelopmental disorders (NDD) remains inconclusive in >50% of the cases. Research analysis of unsolved cases can identify novel candidate genes but is time-consuming, subjective, and hard to compare between labs. The field, therefore, requires automated and standardized assessment methods to prioritize candidates for matchmaking.
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A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition Hum. Mutat. (IF 3.9) Pub Date : 2022-08-23 DaNae R. Woodard, Steffi Daniel, Emi Nakahara, Ali Abbas, Sophia M. DiCesare, Gracen E. Collier, John D. Hulleman
Fibulin-3 (F3 or EFEMP1) is a disulfide-rich, secreted glycoprotein necessary for maintaining extracellular matrix (ECM) and connective tissue integrity. Three studies have identified distinct autosomal recessive F3 mutations in individuals with Marfan Syndrome-like phenotypes. Herein, we characterize how one of these mutations, c.163T>C; p.Cys55Arg (C55R), disrupts F3 secretion, quaternary structure
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach Hum. Mutat. (IF 3.9) Pub Date : 2022-08-18 Mads Thomassen, Romy L. S. Mesman, Thomas V. O. Hansen, Mireia Menendez, Maria Rossing, Ada Esteban-Sánchez, Emma Tudini, Therese Törngren, Michael T. Parsons, Inge S. Pedersen, Soo H. Teo, Torben A. Kruse, Pål Møller, Åke Borg, Uffe B. Jensen, Lise L. Christensen, Christian F. Singer, Daniela Muhr, Marta Santamarina, Rita Brandao, Brage S. Andresen, Bing-Jian Feng, Daffodil Canson, Marcy E. Richardson
Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative
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Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest Hum. Mutat. (IF 3.9) Pub Date : 2022-08-10 Xiaomei Tong, Jiamin Jin, Zhanhong Hu, Yingyi Zhang, Heng-Yu Fan, Yin-Li Zhang, Songying Zhang
The subcortical maternal complex (SCMC), composed of several maternal-effect genes, is vital for the development of oocytes and early embryos. Variants of SCMC-encoding genes (NLRP2, NLRP5, TLE6, PADI6, and KHDC3L, but not OOEP and ZBED3) are associated with human oocyte maturation dysfunction, fertilization failure, and early embryonic arrest. In this study, we enrolled 118 Chinese patients who experienced
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Front Cover, Volume 43, Issue 9 Hum. Mutat. (IF 3.9) Pub Date : 2022-08-03 Qi Liu, Muhammad Faaras Iqbal, Tahir Yaqub, Sehrish Firyal, Yiqiang Zhao, Mark Stoneking, Mingkun Li
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Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders Hum. Mutat. (IF 3.9) Pub Date : 2022-07-29 Michael A. Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S. Fletcher, Florian Cherick, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas
An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can
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De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder Hum. Mutat. (IF 3.9) Pub Date : 2022-07-29 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
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Expanding the phenotypic variability of MORC2 gene mutations: From Charcot-Marie-Tooth disease to late-onset pure motor neuropathy Hum. Mutat. (IF 3.9) Pub Date : 2022-07-29 Arnaud Jacquier, Shams Ribault, Michel Mendes, Nicolas Lacoste, Valérie Risson, Julien Carras, Philippe Latour, Aleksandra Nadaj-Pakleza, Tanya Stojkovic, Laurent Schaeffer
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Characterization of a possible founder synonymous variant in TECTA in multiple individuals with autosomal recessive hearing loss Hum. Mutat. (IF 3.9) Pub Date : 2022-07-23 Robert Chen, Maria Alejandra Diaz-Miranda, Erfan Aref-Eshghi, Tiffiney R. Hartman, Christopher Griffith, Jennifer L. Morrison, Patricia G. Wheeler, Erin Torti, Gabriele Richard, Margaret Kenna, Elizabeth T. Dechene, Nancy B. Spinner, Renkui Bai, Laura K. Conlin, Ian D. Krantz, Sami S. Amr, Minjie Luo
Synonymous variants have been shown to alter the correct splicing of pre-mRNAs and generate disease-causing transcripts. These variants are not an uncommon etiology of genetic disease; however, they are frequently overlooked during genetic testing in the absence of functional and clinical data. Here, we describe the occurrence of a synonymous variant [NM_005422.4 (TECTA):c.327C>T, p.(Gly109=)] in seven
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Multiple mechanisms contribute to the phenotypic effects of synonymous variants Hum. Mutat. (IF 3.9) Pub Date : 2022-07-16 Upendra Katneni, Chava Kimchi-Sarfaty
We read with great interest the work of Zhang et. al.
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Front Cover, Volume 43, Issue 8 Hum. Mutat. (IF 3.9) Pub Date : 2022-07-15 Andreas Laner, Ales Maver, Johan T. den Dunnen