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Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 Tanner D Jensen, Bohan Ni, Chloe Reuter, John E Gorzynski, Sarah Fazal, Devon E Bonner, Rachel Allison Ungar, Pagé C Goddard, Archana Natarajan Raja, Euan A Ashley, Jonathan A Bernstein, Stephan Zuchner, Undiagnosed Diseases Network, Michael D Greicius, Stephen B Montgomery, Michael C Schatz, Matthew T Wheeler, Alexis Battle
Rare structural variants (SVs) – insertions, deletions, and complex rearrangements – can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore long-read genomes of 68 individuals from the Undiagnosed Disease Network (UDN) with no previously identified diagnostic mutations from short-read sequencing. Using our optimized SV detection
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Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 Sarah Silverstein, Rotem Orbach, Safoora Syeda, Reghan Foley, Svetlana Gorokhova, Katherine G Meilleur, Meganne E Leach, Prech Uapinyoying, Katherine R Chao, Sandra Donkervoort, Carsten G Bönnemann
Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NM_001271208.2: c.2079C>A; p.(Cys693Ter) and c.21522+3A>G ) in NEB. Transcriptomic sequencing on patient muscle revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms
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Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 Ayse Keskus, Asher Bryant, Tanveer Ahmad, Byunggil Yoo, Sergey Aganezov, Anton Goretsky, Ataberk Donmez, Lisa A. Lansdon, Isabel Rodriguez, Jimin Park, Yuelin Liu, Xiwen Cui, Joshua Gardner, Brandy McNulty, Samuel Sacco, Jyoti Shetty, Yongmei Zhao, Bao Tran, Giuseppe Narzisi, Adrienne Helland, Daniel E. Cook, Andrew Carroll, Pi-Chuan Chang, Alexey Kolesnikov, Erin K. Molloy, Irina Pushel, Erin Guest
Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex
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Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 Susan M Hiatt, James MJ Lawlor, Lori H Handley, Donald R Latner, Zachary T Bonnstetter, Candice R Finnila, Michelle L Thompson, Lori Beth Boston, Melissa Williams, Ivan Rodriguez Nunez, Jerry Jenkins, Whitley V Kelley, E Martina Bebin, Michael A Lopez, Anna CE Hurst, Bruce R Korf, Jeremy Schmutz, Jane Grimwood, Gregory M Cooper
Variant detection from long-read genome sequencing (lrGS) has proven to be considerably more accurate and comprehensive than variant detection from short-read genome sequencing (srGS). However, the rate at which lrGS can increase molecular diagnostic yield for rare disease is not yet precisely characterized. We performed lrGS using Pacific Biosciences "HiFi" technology on 96 short-read-negative probands
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The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 alfredo iacoangeli, Allison A. Dilliott, Ahmad Al Khleifat, Peter M. Andersen, Nazli A Basak, Johnathan Cooper-Knock, Philippe Corcia, Mamede de Carvalho, Vivian Drory, Jonathan D Glass, Marc Gotkine, Yosef M Lerner, Orla Hardiman, John Landers, Russell McLaughlin, Jesus S Mora Pardina, Karen E Morrison, Susana Pinto, Monica Povedano, Christopher E Shaw, Pamela J Shaw, Vincenzo Silani, Nicola Ticozzi
Recently, large-scale case-control analyses have been prioritized in the study of ALS. Yet the same effort has not been put forward to investigate additive moderate phenotypic effects of genetic variants in genes driving ALS risk, despite case-level evidence suggesting a potential oligogenic risk model. Considering its direct clinical and therapeutic implications, a large-scale robust investigation
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Unraveling the shared genetics of common epilepsies and general cognitive ability. medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 Naz Karadag, Espen Hagen, Alexey A. Shadrin, Dennis Van Der Meer, Kevin S. O'Connell, Zillur Rahman, Gleda Kutrolli, Nadine Parker, Shahram Bahrami, Vera Fominykh, Kjell Heuser, Erik Tauboll, Torill Ueland, Nils Eiel Steen, Srdjan Djurovic, Anders M. Dale, Oleksandr Frei, Ole A. Andreassen, Olav B. Smeland
Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different
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Determining the characteristics of genetic disorders that predict inclusion in newborn genomic sequencing programs medRxiv. Genet. Genom. Med. Pub Date : 2024-03-26 Thomas Minten, Nina B. Gold, Sarah Bick, Sophia Adelson, Nils Gehlenborg, Laura M. Amendola, Francois Boemer, Alison J. Coffey, Nicolas Encina, Bianca E. Russell, Laurent Servais, Kristen L. Sund, Petros Tsipouras, David Bick, Ryan J. Taft, Robert C. Green, ICoNS Gene List Subcommittee
Over 30 international research studies and commercial laboratories are exploring the use of genomic sequencing to screen apparently healthy newborns for genetic disorders. These programs have individualized processes for determining which genes and genetic disorders are queried and reported in newborns. We compared lists of genes from 26 research and commercial newborn screening programs and found
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Phenotypic spectrum of FAM47E-SHROOM3 haplotype composition in a general population sample medRxiv. Genet. Genom. Med. Pub Date : 2024-03-24 Dariush Ghasemi-Semeskandeh, Eva Koenig, Luisa Foco, Nikola Dordevic, Martin Goegele, Johannes Rainer, Markus Ralser, Dianne Acoba, Francisco S. Domingues, Dorien J. M. Peters, Peter P. Pramstaller, Cristian Pattaro
Genome-wide association studies identified a locus on chromosome 4q21.1, spanning the FAM47E, STBD1, CCDC158, and SHROOM3 genes, as associated with kidney function markers. Functional studies implicated SHROOM3, encoding an actin-binding protein involved in cell shaping, into podocyte barrier damage. Despite the locus was also found associated with electrolytes, hematological and cardiovascular traits
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Detection of early-onset severe preeclampsia by cell-free DNA fragmentome medRxiv. Genet. Genom. Med. Pub Date : 2024-03-24 Haiqiang Zhang, Longwei Qiao, Xintao Hu, Chunhua Zhang, Yu Lin, Jingyu Zhao, Xiaojuan wu, Xiaoyan Song, Hui Tang, Ying Xue, Yang Sun, Rijing Ou, Xinxin Wang, Yan Zhang, Xin Jin, Ting Wang
Early-onset severe preeclampsia (EO-PE) is a distinct and highly consequential form of preeclampsia (PE), presenting significant challenges for early detection. Here, we investigated the fragmentation pattern of plasma cell-free DNA (cfDNA) in EO-PE patients. We uncovered that the nucleotide composition at the 5' end (i.e. ends motif) of plasma cfDNA showed a unique pathological preference in EO-PE
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Polygenic susceptibility for multiple sclerosis is associated with working memory in low-performing young adults medRxiv. Genet. Genom. Med. Pub Date : 2024-03-24 Jana Petrovska, David Coynel, Virginie Freytag, Dominique J.-F. de Quervain, Andreas Papassotiropoulos
Background: Multiple sclerosis (MS) is a genetically complex disease with substantial heritability estimates. Besides typical clinical manifestations such as motor and sensory deficits, and fatigue, MS is characterized by structural and functional brain abnormalities, and by cognitive impairment such as decreased working memory (WM) performance. Objectives: This study investigates the possible link
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Trans-ancestral Genome Wide Association Study of Sporadic and Recurrent Miscarriage medRxiv. Genet. Genom. Med. Pub Date : 2024-03-23 Alexandra Reynoso, Priyanka Nandakumar, Jingchunzi Shi, Jessica Bielenberg, 23andMe Research Team, Michael V. Holmes, Stella Aslibekyan
Miscarriage is a common adverse pregnancy outcome, impacting approximately 15% of pregnancies. Herein, we present results of the largest trans-ancestral genome wide association study for miscarriage to date, based on 334,593 cases of sporadic, and 52,087 cases of recurrent miscarriage in the 23andMe, Inc. Research Cohort. We identified 10 novel genome-wide significant associations for sporadic miscarriage
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Deciphering the impact of human M1AP in ZZS-mediated meiotic recombination and male infertility medRxiv. Genet. Genom. Med. Pub Date : 2024-03-22 Nadja Rotte, Jessica E.M. Dunleavy, Michelle Diane Runkel, Daniela Fietz, Adrian Pilatz, Johanna Kuss, Ann-Kristin Dicke, Sofia Boeg Winge, Sara Di Persio, Christian Ruckert, Verena Nordhoff, Hans-Christian Schuppe, Kristian Almstrup, Sabine Kliesch, Nina Neuhaus, Birgit Stallmeyer, Moira K. O'Bryan, Frank Tuettelmann, Corinna Friedrich
Male infertility and meiotic arrest have been linked to M1AP, the gene encoding meiosis I associated protein. In mice, M1AP interacts with the ZZS proteins SHOC1, TEX11, and SPO16, which promote DNA crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by disrupting crossover formation, we screened for biallelic or hemizygous loss-of-function
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Gene-based Hardy-Weinberg equilibrium test using genotype count data identifies novel cancer-related genes medRxiv. Genet. Genom. Med. Pub Date : 2024-03-22 Jo Nishino, Fuyuki Miya, Mamoru Kato
Background: An alternative approach to investigate associations between genetic variants and disease is to examine deviations from the Hardy-Weinberg equilibrium (HWE) in genotype frequencies within a case population, instead of case-control association analysis. The HWE analysis distinctively requires disease cases without the need for controls and demonstrates a notable ability in mapping recessive
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Long-read sequencing of 945 Han individuals identifies novel structural variants associated with phenotypic diversity and disease susceptibility medRxiv. Genet. Genom. Med. Pub Date : 2024-03-22 Jiao Gong, Huiru Sun, Kaiyuan Wang, Yanhui Zhao, Yechao Huang, Qinsheng Chen, Hui Qiao, Yang Gao, Jialin Zhao, Yunchao Ling, Ruifang Cao, Jingze Tan, Qi Wang, Yanyun Ma, Jing Li, Jingchun Luo, Sijia Wang, Jiucun Wang, Guoqing Zhang, Shuhua Xu, Feng Qian, Fang Zhou, Huiru Tang, Dali Li, Fritz J Sedlazeck, Li Jin, Yuting Guan, Shaohua Fan
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Although numerous studies explore SV diversity across global populations and their potential impacts, validation using model systems are needed to confirm the reported genotype-phenotype associations. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported
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Comprehensive analysis of the genetic variation in the LPA gene from short-read sequencing medRxiv. Genet. Genom. Med. Pub Date : 2024-03-22 Raphael Oliver Betschart, Georgios Koliopanos, Paras Garg, Linlin Guo, Massimiliano Rossi, Sebastian Schoenherr, Stefan Blankenberg, Raphael Twerenbold, Tanja Zeller, Andreas Ziegler
Lipoprotein (a) [LP(a)] is a risk factor for cardiovascular diseases and mainly regulated by the complex LPA gene. We investigated the types of variation in the LPA gene and their predictive performance on LP(a) concentration. We determined the Kringle IV-type 2 (KIV-2) copy number (CN) using the DRAGEN LPA Caller (DLC) and a read-depth based CN estimator in 8351 whole genome sequencing samples from
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Genomic Insights for Personalized Care: Motivating At-Risk Individuals Toward Evidence-Based Health Practices medRxiv. Genet. Genom. Med. Pub Date : 2024-03-22 Tony Chen, Giang Pham, Louis Fox, Jingning Zhang, Jinyoung Byun, Younghun Han, Gretchen RB Saunders, Dajiang Liu, Michael J Bray, Alex T Ramsey, James McKay, Laura J Bierut, Christopher Ian Amos, Rayjean J. Hung, Xihong Lin, Haoyu Zhang, Li-Shiun Chen
Lung cancer and tobacco use pose significant global health challenges and require a comprehensive translational roadmap for improved prevention strategies. We propose the GREAT care paradigm (Genomic Informed Care for Motivating High Risk Individuals Eligible for Evidence-based Prevention), which employs polygenic risk scores (PRSs) to stratify disease risk and personalize interventions, such as lung
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NOTCH3 p.Arg1231Cys is Markedly Enriched in South Asians and Associated with Stroke medRxiv. Genet. Genom. Med. Pub Date : 2024-03-21 Juan L Rodriguez-Flores, Shareef Khalid, Neelroop Parikshak, Asif Rasheed, Bin Ye, Manav Kapoor, Joshua Backman, Farshid Sepehrband, Silvio Alessandro DiGioia, Sahar Gelfman, Tanima De, Nilanjana Banerjee, Deepika Sharma, Hector Martinez, Sofia Castaneda, David D Ambrosio, Xingmin A Zhang, Pengcheng Xun, Ellen Tsai, I-Chun Tsai, Regeneron Genetics Center, Maleeha Zaman Khan, Muhammad Jahanzaib, Muhammad
The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691C>T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds
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Assessing germline mutational profile and its clinicopathological associations in Triple Negative Breast Cancer medRxiv. Genet. Genom. Med. Pub Date : 2024-03-21 Jisha John, Ashwini Chandrashekhar Bapat, Siddharth Gahlaut, Naveen Luke, Rahul Kumar, Yashaswi Thakur, Aishwarya Konnur, Namrata Namewar, Ruhi Reddy, Shaheen Shaikh, Rituja Banale, Sanket Nagarkar, Smeeta Nare, George Thomas, Laleh Busheri, Asha Reddy, Devaki Kelkar, Santosh Dixit, Ashraf ul Mannan, Radhakrishnan Sabarinathan, Selvi Radhakrishna, Rupa Mishra, Chaitanyanand B Koppiker
Purpose: Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25%) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are however predominantly representative of
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Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment medRxiv. Genet. Genom. Med. Pub Date : 2024-03-21 Florian Buerger, Daanya Salmanullah, Lorrin Liang, Victoria Gauntner, Kavita Krueger, Maggie Qi, Vineeta Sharma, Alexander Rubin, David Ball, Katharina Lemberg, Ken Saida, Lea Maria Merz, Sanja Sever, Biju Issac, Liang Sun, Sergio Guerrero-Castillo, Alexis C. Gomez, Michelle T. McNulty, Matthew G. Sampson, Mohamed H. Al-Hamed, Mohammed M. Saleh, Mohamed Shalaby, Jameela Kari, James P. Fawcett, Friedhelm
In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants in NOS1AP, encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of NOS1AP/Nos1ap and
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Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs medRxiv. Genet. Genom. Med. Pub Date : 2024-03-21 Chiara Auwerx, Samuel Moix, Zoltán Kutalik, Alexandre Reymond
Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carriers among unrelated white British UK Biobank participants, we performed a phenome-wide association study between the region′s copy
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Utilizing multimodal AI to improve genetic analyses of cardiovascular traits medRxiv. Genet. Genom. Med. Pub Date : 2024-03-21 Yuchen Zhou, Justin T Cosentino, Taedong Yun, Mahantesh I Biradar, Jacqueline Shreibati, Dongbing Lai, Tae-Hwi Schwantes-An, Robert Luben, Zachary R McCaw, Jorgen Engmann, Rui Providencia, Amand Floriaan Schmidt, Patricia B. Munroe, Howard Yang, Andrew Carroll, Anthony P Khawaja, Cory McLean, Babak Behsaz, Farhad Hormozdiari
Electronic health record (EHR) and biobank datasets contain multiple high-dimensional clinical data (HDCD) modalities (e.g., ECG, Photoplethysmography (PPG), and MRI) for each individual. Access to multimodal HDCD provides a unique opportunity for genetic studies of complex traits because different modalities relevant to a single physiological system (e.g., circulatory system) encode complementary
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Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum medRxiv. Genet. Genom. Med. Pub Date : 2024-03-20 Samvida Sudheesh Venkatesh, Laura Wittemans, Duncan Palmer, Nikolas Baya, Teresa Ferreira, Barney Hill, Frederik Heymann Lassen, Melody Parker, Saskia Reibe, Ahmed Elhakeem, Karina Banasik, Mie Bruun, Christian Erikstrup, Bitten Aagaard, Anders Juul, Christina Mikkelsen, Henriette Nielsen, Sisse Ostrowski, Ole Pedersen, Palle Rohde, Erik Soerensen, Henrik Ullum, David Westergaard, Asgeir Haraldsson
Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive
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A Genome-wide Association Study Identifies Novel Genetic Variants Associated with Neck or Shoulder Pain in the UK Biobank (N = 441,757) medRxiv. Genet. Genom. Med. Pub Date : 2024-03-19 Yiwen Tao, Qi Pan, Tengda Cai, Zen Haut Lu, Mainul Haque, Tania Dottorini, Lesley A Colvin, Blair H Smith, Weihua Meng
Neck and shoulder pain are prevalent musculoskeletal disorders that significantly impact the quality of life for a substantial portion of the global population. Studies have shown that women are more susceptible than men. This study aims to discover genetic variants associated with neck or shoulder pain through a genome-wide association study (GWAS), using data from 441,757 participants in the UK Biobank
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A reassessment of Hardy-Weinberg equilibrium filtering in large sample Genomic studies. medRxiv. Genet. Genom. Med. Pub Date : 2024-03-19 Phil J Greer, Anastazie Sedlakova, Mitchell Ellison, Talia DeFrancesco Oranburg, Martin Maiers, David C Whitcomb, Ben Busby
Hardy Weinberg Equilibrium (HWE) is a fundamental principle of population genetics. Adherence to HWE, using a p-value filter, is used as a quality control measure to remove potential genotyping errors prior to certain analyses. Larger sample sizes increase power to differentiate smaller effect sizes, but will also affect methods of quality control. Here, we test the effects of current methods of HWE
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Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities medRxiv. Genet. Genom. Med. Pub Date : 2024-03-19 Douglas Loesch, Manik Garg, Dorota Matelska, Dimitrio Vitsios, Xiao Jiang, Scott C. Ritchie, Benjamin B. Sun, Heiko Runz, Christopher D Whelan, Rury R. Holman, Robert J. Mentz, Filipe A. Moura, Stephen D. Wiviott, Marc S. Sabatine, Miriam S. Udler, Ingrid A. Gause-Nilsson, Slavé Petrovski, Jan Oscarsson, Abhishek Nag, Dirk S. Paul, Michael Inouye
Introduction: Type 2 diabetes (T2D) is a heterogeneous disorder for which disease-causing pathways are incompletely understood. Here, we mapped genetic risk for T2D and its comorbidities to proteins, mechanistic pathways and clinical outcomes using proteogenomic data from a population-scale biobank and two randomized controlled trials. Methods: We tested polygenic scores (PGS) for T2D and its cardiometabolic
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Applying health equity implementation science frameworks to population genetic screening medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Nandana D Rao, Stephanie M Fullerton, Brian H Shirts, Annie T Chen, Nora B Henrikson
Implementation science frameworks with a focus on health equity have emerged to help guide the introduction of new interventions into healthcare and community settings while limiting health disparities. The purpose of this research was to explore the applicability of such frameworks to guide the equitable implementation of population genetic screening programs. We searched PubMed and reference lists
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Mapping structural variants to rare disease genes using long-read whole genome sequencing and trait-relevant polygenic scores medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Cas LeMaster, Carl Schwendinger-Schreck, Bing Ge, Warren Cheung, Jeffrey Johnston, Tomi Pastinen, Craig Smail
Recent studies have revealed the pervasive landscape of rare structural variants (rSVs) present in human genomes. rSVs can have extreme effects on the expression of proximal genes and, in a rare disease context, have been implicated in patient cases where no diagnostic single nucleotide variant (SNV) was found. Approaches for integrating rSVs to date have focused on targeted approaches in known Mendelian
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The link between the ANPEP gene and type 2 diabetes mellitus may be mediated by the disruption of glutathione metabolism and redox homeostasis medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Yaroslava Korvyakova, Iuliia Azarova, Elena Klyosova, Maria Postnikova, Victor Makarenko, Olga Bushueva, Maria Solodilova, Alexey Polonikov
Aminopeptidase N (ANPEP), a membrane-associated ectoenzyme, has been identified as a susceptibility gene for type 2 diabetes (T2D) by genome-wide association and transcriptome studies; however, the mechanisms by which this gene contributes to disease pathogenesis remain unclear. The aim of this study was to determine the comprehensive contribution of ANPEP polymorphisms to T2D risk and annotate the
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Closing the gap: Solving complex medically relevant genes at scale medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Medhat Mahmoud, John Harting, Holly Corbitt, Xiao Chen, Shalini Jhangiani, Harsha Doddapaneni, Qingchang Meng, Christine Lambert, Siyuan Zhang, Primo Baybayan, Geoff Henno, Tina Han, Han Yi, Casey Riegler, Ginger Metcalf, Chinn K Ivan, Michael A Eberle, Sarah Kingan, Tim Farinholt, Carvalho Claudia, Richard A Gibbs, Zev Kronenberg, Donna Muzny, Fritz J Sedlazeck
Comprehending the mechanism behind human diseases with an established heritable component represents the forefront of personalized medicine. Nevertheless, numerous medically important genes are inaccurately represented in short-read sequencing data analysis due to their complexity and repetitiveness or the so-called "dark regions" of the human genome. The advent of PacBio as a long-read platform has
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The benefit of a complete reference genome for cancer structural variant analysis medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Fritz Sedlazeck, Luis F Paulin, Kieran O Neill, Jeremy Fan, Erin Pleasance, Steven J.M. Jones, Vanessa L. Porter
The complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remains challenging
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A RAG Chatbot for Precision Medicine of Multiple Myeloma medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Mujahid Ali Quidwai, Alessandro Lagana
The advent of precision medicine has revolutionized cancer treatment by integrating individual genetic, lifestyle, and environmental factors to tailor patient care (Huang et al., 2020; Ginsburg and Phillips, 2018). However, the complexity and heterogeneity of diseases like Multiple Myeloma (MM) pose significant challenges in leveraging the vast amounts of genomic data and biomedical literature available
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Location of ryanodine receptor type 2 mutation predicts age of onset of sudden death in catecholaminergic polymorphic ventricular tachycardia. A systematic review and meta analysis of case based literature medRxiv. Genet. Genom. Med. Pub Date : 2024-03-16 Halil Beqaj, Leah Sittenfeld, Alexander Chang, Marco Miotto, Haikel dridi, Gloria Willson, Carolyn Martinez Jorge, Jaan Altosaar Li, Steven Reiken, Yang Liu, Zonglin Dai, Andrew R Marks
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia caused by mutations in the ryanodine receptor type 2 (RyR2). Diagnosis of CPVT often occurs after a major cardiac event, thus posing a severe threat to the patient's health. Methods: Publication databases, including PubMed, Scopus, and Embase, were searched for articles on patients with RyR2-CPVT
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A framework for conducting time-varying genome-wide association studies: An application to body mass index across childhood in six multiethnic cohorts medRxiv. Genet. Genom. Med. Pub Date : 2024-03-16 Kimberley Burrows, Anni Heiskala, Jonathan P Bradfield, Zhanna Balkhiyarova, Lijiao Ning, Mathilde Boissel, Yee-Ming Chan, Philippe Froguel, Amelie Bonnefond, Hakon Hakonarson, Alessander Couto Alves, Deborah A Lawlor, Marika Kaakinen, Marjo-Riitta Jarvelin, Struan F.A. Grant, Kate Tilling, Inga Prokopenko, Sylvain Sebert, Mickael Canouil, Nicole M Warrington
Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an
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Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Jessica Gold, Colleen M Kripke, Regeneron Genetics Center, Penn Medicine BioBank, Theodore G Drivas
Numerous studies have underscored the diagnostic and therapeutic potential of exome or genome sequencing in critically ill pediatric populations. However, an equivalent investigation in critically ill adults remains conspicuously absent. We retrospectively analyzed whole exome sequencing (WES) data available through the PennMedicine Biobank (PMBB) from all 365 young adult patients, aged 18-40 years
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Pan-UK Biobank GWAS improves discovery, analysis of genetic architecture, and resolution into ancestry-enriched effects medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Konrad J Karczewski, Rahul Gupta, Masahiro Kanai, Wenhan Lu, Kristin Tsuo, Ying Wang, Raymond K Walters, Patrick Turley, Shawneequa Callier, Nikolas Baya, Duncan S Palmer, Jacqueline I Goldstein, Gopal Sarma, Matthew Solomonson, Nathan Cheng, Sam Bryant, Claire Churchhouse, Caroline M Cusick, Timothy Poterba, John Compitello, Daniel King, Wei Zhou, Cotton Seed, Hilary K Finucane, Mark J Daly, Benjamin
Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses
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Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Jeanne E Savage, Christiaan A de Leeuw, Josefin Werme, Spit for Science Working Group, Danielle M Dick, Danielle Posthuma, Sophie van der Sluis
Background: Gene-environment interaction (GxE) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we utilize a series of genome-wide gene-environment interaction (GWEIS) and in silico annotation methods with the aim of improving gene identification and biological understanding
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Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal cell DNA of individuals with spinocerebellar ataxia type 3 medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G. Monckton
Spinocerebellar ataxia type 3 (SCA3), a currently untreatable disorder, is caused by the expansion of a genetically unstable polyglutamine-encoding complex CAG repeat in the ATXN3 gene. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease
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A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Nawaf Alanzazi, Amer Mahmood, Masood A Shammas, Salman Basit, Aamer Aleem, Sarah Al-Mukhaylid, Zafar Iqbal
The hallmark of Chronic Myeloid Leukemia (CML) is Philadelphia chromosome t(9:22), which leads to formation of BCR-ABL1 fusion oncogene. BCR-ABL1 induces genetic instability, causing the progression of chronic myeloid leukemia (CML) from the manageable Chronic Phase (CP-CML) to the accelerated phase (AP-CML) and ultimately to the lethal blast crisis (BC-CML). The precise mechanism responsible for CML
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Enhanced Data Pre-processing for the Identification of Alzheimer's Disease-Associated SNPs medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Juliana Ferreira Alves, Ricardo Cerri, Eduardo Costa, Luiz Fernando Brito, Alencar Xavier
Alzheimer's Disease (AD) is a complex neurodegenerative disorder that has gained significant attention in scientific research, particularly since the Human Genome Project. Based on twin studies that utilize the resemblance of Alzheimer's disease risk between pairs of twins, it has been found that the overall heritability of the disease is estimated at 0.58. When shared environmental factors are taken
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Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Marco Matejcic, Jamie K Teer, Hannah J Hoehn, Diana B Diaz, Kritika Shankar, Jun Gong, Nathalie T Nguyen, Nicole Lorona, Domenico Coppola, Clifton Fulmer, Ozlen Saglam, Kun Jiang, Douglas Cress, Teresita Munoz-Antonia, Idhaliz Flores, Edna Gordian, Jose A Oliveras Torres, Seth I Felter, Julian A Sanchez, Jason Fleming, Erin M Siegel, Jennifer A Freedman, Julie Dutil, Mariana C Stern, Brooke L Fridley
Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry
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Sparse haplotype-based fine-scale local ancestry inference at scale reveals recent selection on immune responses medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Yaoling Yang, Richard Durbin, Astrid K.N. Iversen, Daniel John Lawson
Increasingly efficient methods for inferring the ancestral origin of genome regions are needed to gain new insights into genetic function and history as biobanks grow in scale. Here we describe two near-linear time algorithms to learn ancestry harnessing the strengths of a Positional Burrows-Wheeler Transform (PBWT). SparsePainter is a faster, sparse replacement of previous model-based `chromosome
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SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Randy L. Parrish, Aron S. Buchman, Shinya Tasaki, Yanling Wang, Denis Avey, Jishu Xu, Philip L. De Jager, David A. Bennett, Michael P. Epstein, Jingjing Yang
Multiple reference panels of a given tissue or multiple tissues often exist, and multiple regression methods could be used for training gene expression imputation models for TWAS. To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear
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Understanding monogenic Parkinson's disease at a global scale medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Johanna Junker, Lara M. Lange, Eva-Juliane Vollstedt, Karisha Roopnarain, Maria Leila M. Doquenia, Azlina Ahmad-Annuar, Micol Avenali, Soraya Bardien, Natascha Bahr, Melina Ellis, Caterina Galandra, Thomas Gasser, Peter Heutink, Anastasia Illarionova, Yuliia Kanana, Ignacio J. Keller Sarmiento, Kishore R. Kumar, Shen-Yang Lim, Harutyun Madoev, Ignacio Mata, Niccolo E. Mencacci, Mike A. Nalls, Shalini
Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, the Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting
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Characterization of the common genetic variation in the Spanish population of Navarre medRxiv. Genet. Genom. Med. Pub Date : 2024-03-14 Alberto Maillo, Estefania Huergo, Maria Apellaniz-Ruiz, Edurne Urrutia, Maria Miranda, Josefa Salgado, Sara Pasalodos-Sanchez, Luna Delgado-Mora, Oscar Teijido, Ibai Goicoechea, Rosario Carmona, Javier Perez-Florido, Virginia Aquino, Daniel Lopez-Lopez, Maria Pena-Chilet, Sergi Beltran, Joaquin Dopazo, Inigo Lasa, Juan Jose Beloqui, Angel Alonso, David Gomez-Cabrero
Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals
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Potential associations of selected polymorphic genetic variants with COVID-19 disease susceptibility and severity medRxiv. Genet. Genom. Med. Pub Date : 2024-03-14 Orsolya Mozner, Edit Szabo, Anna Kulin, Gyorgy Varady, Judit Moldvay, Vivien Vass, Andrea Szentesi, Agoston Janosi, Peter Hegyi, Balazs Sarkadi
In this study, we analyzed the potential associations of selected laboratory and anamnestic parameters, as well as 12 genetic polymorphisms (SNPs), with clinical COVID-19 occurrence and severity in 869 hospitalized patients. The SNPs analyzed by qPCR were selected based on population-wide genetic (GWAS) data previously indicating association with the severity of COVID-19. We confirmed the associations
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Medically relevant tandem repeats in nanopore sequencing of control cohorts medRxiv. Genet. Genom. Med. Pub Date : 2024-03-14 Wouter De Coster, Ida Hoijer, Inge Bruggeman, Svenn D'Hert, Malin Melin, Adam Ameur, Rosa Rademakers
Research and diagnostics for medically relevant tandem repeats and repeat expansions are hampered by the lack of population-scale databases. We attempt to fill this gap using our pathSTR web tool, which leverages long-read sequencing of large cohorts to determine repeat length and sequence composition in the general population. The current version includes 878 individuals of the 1000 Genomes Project
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Unlocking the Treatment of Facioscapulohumeral Muscular Dystrophy Type 2: The Bisphenol Connection medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Saed Sayad, Mark Hiatt, Hazem Mustafa
Background. Facioscapulohumeral muscular dystrophy type 2 (FSHD2) poses a significant challenge within the domain of neuromuscular disorders, marked by a progressive decline in muscle strength accompanied by tissue wasting. FSHD2 results from chromosomal deletions triggering the activation of a dormant gene known as DUX4. While DUX4 typically regulates early embryonic development, its activation in
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Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Nora I. Strom, Zachary F Gerring, Marco Galimberti, Dongmei Yu, Matthew W Halvorsen, Abdel Abdellaoui, Cristina Rodriguez-Fontenla, Julia M Sealock, Tim Bigdeli, Jonathan R. I. Coleman, Behrang Mahjani, Jackson G Thorp, Katharina Bey, Christie L Burton, Jurjen J Luykx, Gwyneth Zai, Silvia Alemany, Christine Andre, Kathleen D Askland, Nerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O. Joseph
Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent
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Leveraging cancer mutation data to predict the pathogenicity of germline missense variants medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Bushra Haque, David Cheerie, Amy Pan, Meredith Curtis, Thomas Nalpathamkalam, Jimmy Nguyen, Celine Salhab, Bhooma Thiruvahindrapura, Jade Zhang, Madeline Couse, Taila Hartley, Michelle M Morrow, E Magda Price, Susan Walker, David Malkin, Frederick P Roth, Gregory Costain
Background: Innovative and easy-to-implement strategies are needed to improve the pathogenicity assessment of rare germline missense variants. Somatic cancer driver mutations identified through large-scale tumor sequencing studies often impact genes that are also associated with rare Mendelian disorders. The use of cancer mutation data to aid in the interpretation of germline missense variants, regardless
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Characterizing genetic profiles for high triglyceride levels in U.S. patients of African ancestry medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Lan Jiang, Srushti Gangireddy, Alyson Dickson, Vivian Kawai, Nancy J Cox, Macrae Linton, Wei-Qi Wei, C. Michael Stein, QiPing Feng
Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated circulating triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry (EA). However, relatively little is known about the contribution of genetic variation to HTG in people of AA, potentially constraining research
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Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk medRxiv. Genet. Genom. Med. Pub Date : 2024-03-12 Hannes F Bode, Liang He, Jacob Hjelmborg, Jaakko Kaprio, Miina Ollikainen
Background: Assessment of breast cancer (BC) risk generally relies on mammography, family history, reproductive history, and genotyping of major mutations. However, assessing the impact of environmental factors, such as lifestyle, health related behavior or external exposures, is still challenging. DNA methylation (DNAm), capturing both genetic and environmental effects, presents a promising opportunity
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Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics medRxiv. Genet. Genom. Med. Pub Date : 2024-03-11 R. Taylor Sundby, Jeffrey J. Szymanski, Alexander Pan, Paul A. Jones, Sana Z. Mahmood, Olivia H. Reid, Divya Srihari, Amy E Armstrong, Stacey Chamberlain, Sanita Burgic, Kara Weekley, Béga Murray, Sneh Patel, Faridi Qaium, Andrea N. Lucas, Margaret Fagan, Anne Dufek, Christian F. Meyer, Natalie B. Collins, Christine A. Pratilas, Eva Dombi, Andrea M. Gross, AeRang Kim, John S.A Chrisinger, Carina A
Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 121 NF1 patients and 21 healthy controls
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Systematic Review and Meta-Analysis: Research Using the Autism Polygenic Score medRxiv. Genet. Genom. Med. Pub Date : 2024-03-09 Melanie M. de Wit, Morgan J. Morgan, Ilan Libedinsky, Chloe Austerberry, Sander Begeer, Abdel Abdellaoui, Angelica Ronald, Tinca J.C. Polderman
Objective: Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The autism polygenic score, derived from the latest autism case-control meta-genome-wide association studies, captures some of the accumulated influence of common genetic variants on autism. We reviewed and meta-analyzed published studies that assessed the relationship
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Genome-wide association study identifies new loci associated with OCD medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Nora I Strom, Matthew W Halvorsen, Chao Tian, Christian Rück, Gerd Kvale, Bjarne Hansen, Jonas Bybjerg-Grauholm, Jakob Grove, Julia Boberg, Judith Becker Nissen, Thomas Damm Als, Thomas Werge, Elles de Schipper, Bengt Fundin, Christina Hultman, Kira D Höffler, Nancy Pedersen, Sven Sandin, Cynthia Bulik, Mikael Landén, Elinor Karlsson, Kristen Hagen, Kerstin Lindblad-Toh, Nordic OCD and Related Disorders
To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28\% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS
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Locus-specific stratification and prioritization unveil high risk genes underlying hyperuricemia medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Jing Zhang, Yue Guo, Luyu Gong, Limei Xia, Qiaoqiao Liu, Kangchun Wang, Qi Wang, Zhaojun Liu, Zhaohui Qin, Shaolin Shi, Jingping Yang
The development of alternative medications for urate-lowering therapies is imperative for patients that are intolerant to current treatments. Despite GWAS have identified hundreds of loci associated with serum urate levels, the mechanistic understanding and discovery of drug targets remain difficult. This difficulty arises from the multiple-independent-associations challenge in the genomic studies
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A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Pavithra Nagarajan, Thomas W Winkler, Amy R Bentley, Clint L Miller, Aldi T Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael R Brown, John L Morrison, Ayush Giri, Jeffrey R O'Connell, Traci M Bartz, Lisa de las Fuentes, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Zhijie Huang, Mart Kals, Minjung Kho, Christophe Lefevre, Jian'an Luan, Leo-Pekka Lyytikainen, Massimo Mangino, Yuri Milaneschi
Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811
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GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Hellen Lesmann, Alexander Hustinx, Shahida Moosa, Elaine Marchi, Pilar Caro, Ibrahim M. Abdelrazek, Jean Tori Pantel, Hannah Klinkhammer, Merle ten Hagen, Tom Kamphans, Wolfgang Meiswinkel, Jing-Mei Li, Behnam Javanmardi, Alexej Knaus, Annette Uwineza, Cordula Knopp, Tinatin Tkemaladze, Miriam Elbracht, Larissa Mattern, Rami Abou Jamra, Clara Velmans, Vincent Strehlow, Himanshu Goel, Beatriz Carvalho
Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare
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Nanopore sequencing of 1000 Genomes Project samples to build a comprehensive catalog of human genetic variation medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Jonas A Gustafson, Sophia B Gibson, Nikhita Damaraju, Miranda PG Zalusky, Kendra Hoekzema, David Twesigomwe, Lei Yang, Anthony A Snead, Phillip A Richmond, Wouter De Coster, Nathan D Olson, Andrea Guarracino, Qiuhui Li, Angela L Miller, Joy Goffena, Zachery Anderson, Sophie HR Storz, Sydney A Ward, Maisha Sinha, Claudia Gonzaga-Jauregui, Wayne E Clarke, Anna O Basile, Andre Corvelo, Catherine E Reeves
Less than half of individuals with a suspected Mendelian condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control datasets for variant filtering and prioritization has made tertiary analysis of LRS
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The performance of AlphaMissense to identify genes causing disease medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Yiheng Chen, Guillaume Butler-Laporte, Kevin Y.H. Liang, Yann Ilboudo, Summaira Yasmeen, Takayoshi Sasako, Claudia Langenberg, Celia MT Greenwood, J Brent Richards
A novel algorithm, AlphaMissense, has been shown to have an improved ability to predict the pathogenicity of rare missense genetic variants. However, it is not known whether AlphaMissense improves the ability of gene-based testing to identify disease-causing genes. Using whole-exome sequencing data from the UK Biobank, we compared gene-based association analysis strategies including sets of deleterious
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Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Sarah L Stenton, Vikas Pejaver, Timothy Bergquist, Leslie G Biesecker, Alicia B Byrne, Emily Nadeau, Marc S Greenblatt, Steven Harrison, Sean Tavtigian, Predrag Radivojac, Steven E Brenner, Anne O'Donnell-Luria, ClinGen Sequence Variant Interpretation Working Group
Purpose: To investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations. Methods: Missense variants from the genome sequences of 300 probands from the Rare Genomes Project with suspected rare disease were analyzed using computational prediction tools able to reach PP3_Strong