NPJ Genomic Medicine最新文献

{"title":"Genomes in clinical care","authors":"Olaf Riess, Marc Sturm, Benita Menden, Alexandra Liebmann, German Demidov, Dennis Witt, Nicolas Casadei, Jakob Admard, Leon Schütz, Stephan Ossowski, Stacie Taylor, Sven Schaffer, Christopher Schroeder, Andreas Dufke, Tobias Haack","doi":"10.1038/s41525-024-00402-2","DOIUrl":"https://doi.org/10.1038/s41525-024-00402-2","url":null,"abstract":"<p>In the era of precision medicine, genome sequencing (GS) has become more affordable and the importance of genomics and multi-omics in clinical care is increasingly being recognized. However, how to scale and effectively implement GS on an institutional level remains a challenge for many. Here, we present Genome First and Ge-Med, two clinical implementation studies focused on identifying the key pillars and processes that are required to make routine GS and predictive genomics a reality in the clinical setting. We describe our experience and lessons learned for a variety of topics including test logistics, patient care processes, data reporting, and infrastructure. Our model of providing clinical care and comprehensive genomic analysis from a single source may be used by other centers with a similar structure to facilitate the implementation of omics-based personalized health concepts in medicine.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"29 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140129322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.","authors":"Dhanya Ramachandran, Jonathan P Tyrer, Stefan Kommoss, Anna DeFazio, Marjorie J Riggan, Penelope M Webb, Peter A Fasching, Diether Lambrechts, María J García, Cristina Rodríguez-Antona, Marc T Goodman, Francesmary Modugno, Kirsten B Moysich, Beth Y Karlan, Jenny Lester, Susanne K Kjaer, Allan Jensen, Estrid Høgdall, Ellen L Goode, William A Cliby, Amanika Kumar, Chen Wang, Julie M Cunningham, Stacey J Winham, Alvaro N Monteiro, Joellen M Schildkraut, Daniel W Cramer, Kathryn L Terry, Linda Titus, Line Bjorge, Liv Cecilie Vestrheim Thomsen, Tanja Pejovic, Claus K Høgdall, Iain A McNeish, Taymaa May, David G Huntsman, Jacobus Pfisterer, Ulrich Canzler, Tjoung-Won Park-Simon, Willibald Schröder, Antje Belau, Lars Hanker, Philipp Harter, Jalid Sehouli, Rainer Kimmig, Nikolaus de Gregorio, Barbara Schmalfeldt, Klaus Baumann, Felix Hilpert, Alexander Burges, Boris Winterhoff, Peter Schürmann, Lisa-Marie Speith, Peter Hillemanns, Andrew Berchuck, Sharon E Johnatty, Susan J Ramus, Georgia Chenevix-Trench, Paul D P Pharoah, Thilo Dörk, Florian Heitz","doi":"10.1038/s41525-024-00395-y","DOIUrl":"10.1038/s41525-024-00395-y","url":null,"abstract":"<p><p>Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10^-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"19"},"PeriodicalIF":4.7,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10915171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.","authors":"Jil D Stegmann, Jeshurun C Kalanithy, Gabriel C Dworschak, Nina Ishorst, Enrico Mingardo, Filipa M Lopes, Yee Mang Ho, Phillip Grote, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Steve Seltzsam, Shirlee Shril, Friedhelm Hildebrandt, Felix Boschann, André Heinen, Angad Jolly, Katherine Myers, Kim McBride, Mir Reza Bekheirnia, Nasim Bekheirnia, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Annalaura Torella, Michele Pinelli, Valeria Capra, Andrea Accogli, Silvia Maitz, Alice Spano, Rory J Olson, Eric W Klee, Brendan C Lanpher, Se Song Jang, Jong-Hee Chae, Philipp Steinbauer, Dietmar Rieder, Andreas R Janecke, Julia Vodopiutz, Ida Vogel, Jenny Blechingberg, Jennifer L Cohen, Kacie Riley, Victoria Klee, Laurence E Walsh, Matthias Begemann, Miriam Elbracht, Thomas Eggermann, Arzu Stoppe, Kyra Stuurman, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Maureen S Mulhern, Tristan T Sands, Cheryl Cytrynbaum, Rosanna Weksberg, Federica Isidori, Tommaso Pippucci, Giulia Severi, Francesca Montanari, Michael C Kruer, Somayeh Bakhtiari, Hossein Darvish, Heiko Reutter, Gregor Hagelueken, Matthias Geyer, Adrian S Woolf, Jennifer E Posey, James R Lupski, Benjamin Odermatt, Alina C Hilger","doi":"10.1038/s41525-024-00398-9","DOIUrl":"10.1038/s41525-024-00398-9","url":null,"abstract":"<p><p>CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"18"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10907620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review.","authors":"Stephen F Kingsmore, Russell Nofsinger, Kasia Ellsworth","doi":"10.1038/s41525-024-00404-0","DOIUrl":"10.1038/s41525-024-00404-0","url":null,"abstract":"<p><p>Single locus (Mendelian) diseases are a leading cause of childhood hospitalization, intensive care unit (ICU) admission, mortality, and healthcare cost. Rapid genome sequencing (RGS), ultra-rapid genome sequencing (URGS), and rapid exome sequencing (RES) are diagnostic tests for genetic diseases for ICU patients. In 44 studies of children in ICUs with diseases of unknown etiology, 37% received a genetic diagnosis, 26% had consequent changes in management, and net healthcare costs were reduced by $14,265 per child tested by URGS, RGS, or RES. URGS outperformed RGS and RES with faster time to diagnosis, and higher rate of diagnosis and clinical utility. Diagnostic and clinical outcomes will improve as methods evolve, costs decrease, and testing is implemented within precision medicine delivery systems attuned to ICU needs. URGS, RGS, and RES are currently performed in <5% of the ~200,000 children likely to benefit annually due to lack of payor coverage, inadequate reimbursement, hospital policies, hospitalist unfamiliarity, under-recognition of possible genetic diseases, and current formatting as tests rather than as a rapid precision medicine delivery system. The gap between actual and optimal outcomes in children in ICUs is currently increasing since expanded use of URGS, RGS, and RES lags growth in those likely to benefit through new therapies. There is sufficient evidence to conclude that URGS, RGS, or RES should be considered in all children with diseases of uncertain etiology at ICU admission. Minimally, diagnostic URGS, RGS, or RES should be ordered early during admissions of critically ill infants and children with suspected genetic diseases.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"17"},"PeriodicalIF":4.7,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10899612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA and RNA base editors can correct the majority of pathogenic single nucleotide variants.","authors":"Ariel Dadush, Rona Merdler-Rabinowicz, David Gorelik, Ariel Feiglin, Ilana Buchumenski, Lipika R Pal, Shay Ben-Aroya, Eytan Ruppin, Erez Y Levanon","doi":"10.1038/s41525-024-00397-w","DOIUrl":"10.1038/s41525-024-00397-w","url":null,"abstract":"<p><p>The majority of human genetic diseases are caused by single nucleotide variants (SNVs) in the genome sequence. Excitingly, new genomic techniques known as base editing have opened efficient pathways to correct erroneous nucleotides. Due to reliance on deaminases, which have the capability to convert A to I(G) and C to U, the direct applicability of base editing might seem constrained in terms of the range of mutations that can be reverted. In this evaluation, we assess the potential of DNA and RNA base editing methods for treating human genetic diseases. Our findings indicate that 62% of pathogenic SNVs found within genes can be amended by base editing; 30% are G>A and T>C SNVs that can be corrected by DNA base editing, and most of them by RNA base editing as well, and 29% are C>T and A>G SNVs that can be corrected by DNA base editing directed to the complementary strand. For each, we also present several factors that affect applicability such as bystander and off-target occurrences. For cases where editing the mismatched nucleotide is not feasible, we introduce an approach that calculates the optimal substitution of the deleterious amino acid with a new amino acid, further expanding the scope of applicability. As personalized therapy is rapidly advancing, our demonstration that most SNVs can be treated by base editing is of high importance. The data provided will serve as a comprehensive resource for those seeking to design therapeutic base editors and study their potential in curing genetic diseases.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"16"},"PeriodicalIF":5.3,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders","authors":"Kristen M. Wigby, Deanna Brockman, Gregory Costain, Caitlin Hale, Stacie L. Taylor, John Belmont, David Bick, David Dimmock, Susan Fernbach, John Greally, Vaidehi Jobanputra, Shashikant Kulkarni, Elizabeth Spiteri, Ryan J. Taft","doi":"10.1038/s41525-024-00396-x","DOIUrl":"https://doi.org/10.1038/s41525-024-00396-x","url":null,"abstract":"<p>Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12–73%), 33% (6–86%) in cohorts with prior genetic testing, and 33% (9–60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24–100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"4 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139968984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell-transcriptomic analysis informs the lncRNA landscape in metastatic castration resistant prostate cancer.","authors":"Debanjan Saha, Ha X Dang, Meng Zhang, David A Quigley, Felix Y Feng, Christopher A Maher","doi":"10.1038/s41525-024-00401-3","DOIUrl":"10.1038/s41525-024-00401-3","url":null,"abstract":"<p><p>Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer. Although long-noncoding RNAs (lncRNAs) have been implicated in mCRPC, past studies have relied on bulk sequencing methods with low depth and lack of single-cell resolution. Hence, we performed a lncRNA-focused analysis of single-cell RNA-sequencing data (n = 14) from mCRPC biopsies followed by integration with bulk multi-omic datasets. This yielded 389 cell-enriched lncRNAs in prostate cancer cells and the tumor microenvironment (TME). These lncRNAs demonstrated enrichment with regulatory elements and exhibited alterations during prostate cancer progression. Prostate-lncRNAs were correlated with AR mutational status and response to treatment with enzalutamide, while TME-lncRNAs were associated with RB1 deletions and poor prognosis. Finally, lncRNAs identified between prostate adenocarcinomas and neuroendocrine tumors exhibited distinct expression and methylation profiles. Our findings demonstrate the ability of single-cell analysis to refine our understanding of lncRNAs in mCRPC and serve as a resource for future mechanistic studies.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"14"},"PeriodicalIF":5.3,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10891057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139940355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A call for increased inclusivity and global representation in pharmacogenetic testing.","authors":"April Kennedy, Gabriel Ma, Roozbeh Manshaei, Rebekah K Jobling, Raymond H Kim, Tamorah Lewis, Iris Cohn","doi":"10.1038/s41525-024-00403-1","DOIUrl":"10.1038/s41525-024-00403-1","url":null,"abstract":"<p><p>Commercial pharmacogenetic testing panels capture a fraction of the genetic variation underlying medication metabolism and predisposition to adverse reactions. In this study we compared variation in six pharmacogenes detected by whole genome sequencing (WGS) to a targeted commercial panel in a cohort of 308 individuals with family history of pediatric heart disease. In 1% of the cohort, WGS identified rare variants that altered the interpretation of metabolizer status and would thus prevent potential errors in gene-based dosing.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"13"},"PeriodicalIF":5.3,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population","authors":"Ayda Abolhassani, Zohreh Fattahi, Maryam Beheshtian, Mahsa Fadaee, Raheleh Vazehan, Fatemeh Ahangari, Shima Dehdahsi, Mehrshid Faraji Zonooz, Elham Parsimehr, Zahra Kalhor, Fatemeh Peymani, Maryam Mozaffarpour Nouri, Mojgan Babanejad, Khadijeh Noudehi, Fatemeh Fatehi, Shima Zamanian Najafabadi, Fariba Afroozan, Hilda Yazdan, Bita Bozorgmehr, Azita Azarkeivan, Shokouh Sadat Mahdavi, Pooneh Nikuei, Farzad Fatehi, Payman Jamali, Mahmoud Reza Ashrafi, Parvaneh Karimzadeh, Haleh Habibi, Kimia Kahrizi, Shahriar Nafissi, Ariana Kariminejad, Hossein Najmabadi","doi":"10.1038/s41525-024-00393-0","DOIUrl":"https://doi.org/10.1038/s41525-024-00393-0","url":null,"abstract":"<p>Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype–phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"39 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139902070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the efficacy of target adaptive sampling long-read sequencing through hereditary cancer patient genomes.","authors":"Wataru Nakamura, Makoto Hirata, Satoyo Oda, Kenichi Chiba, Ai Okada, Raúl Nicolás Mateos, Masahiro Sugawa, Naoko Iida, Mineko Ushiama, Noriko Tanabe, Hiromi Sakamoto, Shigeki Sekine, Akira Hirasawa, Yosuke Kawai, Katsushi Tokunaga, Shin-Ichi Tsujimoto, Norio Shiba, Shuichi Ito, Teruhiko Yoshida, Yuichi Shiraishi","doi":"10.1038/s41525-024-00394-z","DOIUrl":"10.1038/s41525-024-00394-z","url":null,"abstract":"<p><p>Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"11"},"PeriodicalIF":5.3,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10874402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139898178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}