{"title":"Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand.","authors":"Chalermkiat Kansuttiviwat, Pongtawat Lertwilaiwittaya, Ekkapong Roothumnong, Panee Nakthong, Peerawat Dungort, Chutima Meesamarnpong, Warisara Tansa-Nga, Khontawan Pongsuktavorn, Supakit Wiboonthanasarn, Warunya Tititumjariya, Nannipa Phuphuripan, Chittapat Lertbussarakam, Jantanee Wattanarangsan, Jiraporn Sritun, Kittiporn Punuch, Jirayu Kammarabutr, Pornthira Mutirangura, Wanna Thongnoppakhun, Chanin Limwongse, Manop Pithukpakorn","doi":"10.1038/s41525-024-00400-4","DOIUrl":"10.1038/s41525-024-00400-4","url":null,"abstract":"<p><p>Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"9"},"PeriodicalIF":5.3,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735712","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}
Ilias Goranitis, Yan Meng, Melissa Martyn, Stephanie Best, Sophie Bouffler, Yvonne Bombard, Clara Gaff, Zornitza Stark
{"title":"Eliciting parental preferences and values for the return of additional findings from genomic sequencing.","authors":"Ilias Goranitis, Yan Meng, Melissa Martyn, Stephanie Best, Sophie Bouffler, Yvonne Bombard, Clara Gaff, Zornitza Stark","doi":"10.1038/s41525-024-00399-8","DOIUrl":"10.1038/s41525-024-00399-8","url":null,"abstract":"<p><p>Health economic evidence is needed to inform the design of high-value and cost-effective processes for returning genomic results from analyses for additional findings (AF). This study reports the results of a discrete-choice experiment designed to elicit preferences for the process of returning AF results from the perspective of parents of children with rare conditions and to estimate the value placed on AF analysis. Overall, 94 parents recruited within the Australian Genomics and Melbourne Genomics programmes participated in the survey, providing preferences in a total of 1128 choice scenarios. Statistically significant preferences were identified for the opportunity to change the choices made about AF; receiving positive AF in person from a genetic counsellor; timely access to a medical specialist and high-quality online resources; receiving automatic updates through a secure online portal if new information becomes available; and lower costs. For AF uptake rates ranging between 50-95%, the mean per person value from AF analysis was estimated at AU$450-$1700 (US$300-$1140). The findings enable the design of a value-maximising process of analysis for AF in rare-disease genomic sequencing.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"10"},"PeriodicalIF":5.3,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10867021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735711","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}
Claude Bhérer, Robert Eveleigh, Katerina Trajanoska, Janick St-Cyr, Antoine Paccard, Praveen Nadukkalam Ravindran, Elizabeth Caron, Nimara Bader Asbah, Peyton McClelland, Clare Wei, Iris Baumgartner, Marc Schindewolf, Yvonne Döring, Danielle Perley, François Lefebvre, Pierre Lepage, Mathieu Bourgey, Guillaume Bourque, Jiannis Ragoussis, Vincent Mooser, Daniel Taliun
{"title":"A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome.","authors":"Claude Bhérer, Robert Eveleigh, Katerina Trajanoska, Janick St-Cyr, Antoine Paccard, Praveen Nadukkalam Ravindran, Elizabeth Caron, Nimara Bader Asbah, Peyton McClelland, Clare Wei, Iris Baumgartner, Marc Schindewolf, Yvonne Döring, Danielle Perley, François Lefebvre, Pierre Lepage, Mathieu Bourgey, Guillaume Bourque, Jiannis Ragoussis, Vincent Mooser, Daniel Taliun","doi":"10.1038/s41525-024-00390-3","DOIUrl":"10.1038/s41525-024-00390-3","url":null,"abstract":"<p><p>Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call \"Whole Exome Genome Sequencing\" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"8"},"PeriodicalIF":5.3,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10850497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139703051","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}
Hannah E. Bergom, Laura A. Sena, Abderrahman Day, Benjamin Miller, Carly D. Miller, John R. Lozada, Nicholas Zorko, Jinhua Wang, Eugene Shenderov, Francisco Pereira Lobo, Fernanda Caramella-Pereira, Luigi Marchionni, Charles G. Drake, Tamara Lotan, Angelo M. De Marzo, Justin Hwang, Emmanuel S. Antonarakis
{"title":"Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer","authors":"Hannah E. Bergom, Laura A. Sena, Abderrahman Day, Benjamin Miller, Carly D. Miller, John R. Lozada, Nicholas Zorko, Jinhua Wang, Eugene Shenderov, Francisco Pereira Lobo, Fernanda Caramella-Pereira, Luigi Marchionni, Charles G. Drake, Tamara Lotan, Angelo M. De Marzo, Justin Hwang, Emmanuel S. Antonarakis","doi":"10.1038/s41525-024-00392-1","DOIUrl":"https://doi.org/10.1038/s41525-024-00392-1","url":null,"abstract":"<p>Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic <i>MSH2</i> and <i>MSH6</i> alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (“hot nodule”), while the second displayed significantly fewer infiltrating lymphocytes (“cold nodule”). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (<i>CD274</i>) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"11 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139514901","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":"Whole genome sequencing enables new genetic diagnosis for inherited retinal diseases by identifying pathogenic variants","authors":"Xubing Liu, Fangyuan Hu, Daowei Zhang, Zhe Li, Jianquan He, Shenghai Zhang, Zhenguo Wang, Yingke Zhao, Jiawen Wu, Chen Liu, Chenchen Li, Xin Li, Jihong Wu","doi":"10.1038/s41525-024-00391-2","DOIUrl":"https://doi.org/10.1038/s41525-024-00391-2","url":null,"abstract":"<p>Inherited retinal diseases (IRDs) are a group of common primary retinal degenerative disorders. Conventional genetic testing strategies, such as panel-based sequencing and whole exome sequencing (WES), can only elucidate the genetic etiology in approximately 60% of IRD patients. Studies have suggested that unsolved IRD cases could be attributed to previously undetected structural variants (SVs) and intronic variants in IRD-related genes. The aim of our study was to obtain a definitive genetic diagnosis by employing whole genome sequencing (WGS) in IRD cases where the causative genes were inconclusive following an initial screening by panel sequencing. A total of 271 unresolved IRD patients and their available family members (<i>n</i> = 646) were screened using WGS to identify pathogenic SVs and intronic variants in 792 known ocular disease genes. Overall, 13% (34/271) of IRD patients received a confirmed genetic diagnosis, among which 7% were exclusively attributed to SVs, 4% to a combination of single nucleotide variants (SNVs) and SVs while another 2% were linked to intronic variants. 22 SVs, 3 deep-intronic variants, and 2 non-canonical splice-site variants across 14 IRD genes were identified in the entire cohort. Notably, all of these detected SVs and intronic variants were novel pathogenic variants. Among those, 74% (20/27) of variants were found in genes causally linked to Retinitis Pigmentosa (RP), with the gene <i>EYS</i> being the most frequently affected by SVs. The identification of SVs and intronic variants through WGS enhances the genetic diagnostic yield of IRDs and broadens the mutational spectrum of known IRD-associated genes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"4 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139507133","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}
Gonench Kilich, Kelly Hassey, Edward M Behrens, Marni Falk, Adeline Vanderver, Daniel J Rader, Patrick J Cahill, Anna Raper, Zhe Zhang, Dawn Westerfer, Tanaya Jadhav, Laura Conlin, Kosuke Izumi, Ramakrishnan Rajagopalan, Kathleen E Sullivan
{"title":"Kagami Ogata syndrome: a small deletion refines critical region for imprinting.","authors":"Gonench Kilich, Kelly Hassey, Edward M Behrens, Marni Falk, Adeline Vanderver, Daniel J Rader, Patrick J Cahill, Anna Raper, Zhe Zhang, Dawn Westerfer, Tanaya Jadhav, Laura Conlin, Kosuke Izumi, Ramakrishnan Rajagopalan, Kathleen E Sullivan","doi":"10.1038/s41525-023-00389-2","DOIUrl":"10.1038/s41525-023-00389-2","url":null,"abstract":"<p><p>Kagami-Ogata syndrome is a rare imprinting disorder and its phenotypic overlap with multiple different etiologies hampers diagnosis. Genetic etiologies include paternal uniparental isodisomy (upd(14)pat), maternal allele deletions of differentially methylated regions (DMR) in 14q32.2 or pure primary epimutations. We report a patient with Kagami-Ogata syndrome and an atypical diagnostic odyssey with several negative standard-of-care genetic tests followed by epigenetic testing using methylation microarray and a targeted analysis of whole-genome sequencing to reveal a 203 bp deletion involving the MEG3 transcript and MEG3:TSS-DMR. Long-read sequencing enabled the simultaneous detection of the deletion, phasing, and biallelic hypermethylation of the MEG3:TSS-DMR region in a single assay. This case highlights the challenges in the sequential genetic testing paradigm, the utility of long-read sequencing as a single comprehensive diagnostic assay, and the smallest reported deletion causing Kagami-Ogata syndrome allowing important insights into the mechanism of imprinting effects at this locus.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"5"},"PeriodicalIF":5.3,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10784583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139425200","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}
Timothy H Ciesielski, Giorgio Sirugo, Sudha K Iyengar, Scott M Williams
{"title":"Characterizing the pathogenicity of genetic variants: the consequences of context.","authors":"Timothy H Ciesielski, Giorgio Sirugo, Sudha K Iyengar, Scott M Williams","doi":"10.1038/s41525-023-00386-5","DOIUrl":"10.1038/s41525-023-00386-5","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"3"},"PeriodicalIF":5.3,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10776585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403820","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}
Charles H Jones, John R Androsavich, Nina So, Matthew P Jenkins, Derek MacCormack, Andrew Prigodich, Verna Welch, Jane M True, Mikael Dolsten
{"title":"Breaking the mold with RNA-a \"RNAissance\" of life science.","authors":"Charles H Jones, John R Androsavich, Nina So, Matthew P Jenkins, Derek MacCormack, Andrew Prigodich, Verna Welch, Jane M True, Mikael Dolsten","doi":"10.1038/s41525-023-00387-4","DOIUrl":"10.1038/s41525-023-00387-4","url":null,"abstract":"<p><p>In the past decade, RNA therapeutics have gone from being a promising concept to one of the most exciting frontiers in healthcare and pharmaceuticals. The field is now entering what many call a renaissance or \"RNAissance\" which is being fueled by advances in genetic engineering and delivery systems to take on more ambitious development efforts. However, this renaissance is occurring at an unprecedented pace, which will require a different way of thinking if the field is to live up to its full potential. Recognizing this need, this article will provide a forward-looking perspective on the field of RNA medical products and the potential long-term innovations and policy shifts enabled by this revolutionary and game-changing technological platform.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"2"},"PeriodicalIF":5.3,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10776758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403819","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":"Highly efficient capture approach for the identification of diverse inherited retinal disorders.","authors":"Hsiao-Jung Kao, Ting-Yi Lin, Feng-Jen Hsieh, Jia-Ying Chien, Erh-Chan Yeh, Wan-Jia Lin, Yi-Hua Chen, Kai-Hsuan Ding, Yu Yang, Sheng-Chu Chi, Ping-Hsing Tsai, Chih-Chien Hsu, De-Kuang Hwang, Hsien-Yang Tsai, Mei-Ling Peng, Shi-Huang Lee, Siu-Fung Chau, Chen Yu Chen, Wai-Man Cheang, Shih-Jen Chen, Pui-Yan Kwok, Shih-Hwa Chiou, Mei-Yeh Jade Lu, Shun-Ping Huang","doi":"10.1038/s41525-023-00388-3","DOIUrl":"10.1038/s41525-023-00388-3","url":null,"abstract":"<p><p>Our study presents a 319-gene panel targeting inherited retinal dystrophy (IRD) genes. Through a multi-center retrospective cohort study, we validated the assay's effectiveness and clinical utility and characterized the mutation spectrum of Taiwanese IRD patients. Between January 2018 and May 2022, 493 patients in 425 unrelated families, all initially suspected of having IRD without prior genetic diagnoses, underwent detailed ophthalmic and physical examinations (with extra-ocular features recorded) and genetic testing with our customized panel. Disease-causing variants were identified by segregation analysis and clinical interpretation, with validation via Sanger sequencing. We achieved a read depth of >200× for 94.2% of the targeted 1.2 Mb region. 68.5% (291/425) of the probands received molecular diagnoses, with 53.9% (229/425) resolved cases. Retinitis pigmentosa (RP) is the most prevalent initial clinical impression (64.2%), and 90.8% of the cohort have the five most prevalent phenotypes (RP, cone-rod syndrome, Usher's syndrome, Leber's congenital amaurosis, Bietti crystalline dystrophy). The most commonly mutated genes of probands that received molecular diagnosis are USH2A (13.7% of the cohort), EYS (11.3%), CYP4V2 (4.8%), ABCA4 (4.5%), RPGR (3.4%), and RP1 (3.1%), collectively accounted for 40.8% of diagnoses. We identify 87 unique unreported variants previously not associated with IRD and refine clinical diagnoses for 21 patients (7.22% of positive cases). We developed a customized gene panel and tested it on the largest Taiwanese cohort, showing that it provides excellent coverage for diverse IRD phenotypes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"4"},"PeriodicalIF":5.3,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10776681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403821","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}
Yusuph Mavura, Nuriye Sahin-Hodoglugil, Ugur Hodoglugil, Mark Kvale, Pierre-Marie Martin, Jessica Van Ziffle, W Patrick Devine, Sara L Ackerman, Barbara A Koenig, Pui-Yan Kwok, Mary E Norton, Anne Slavotinek, Neil Risch
{"title":"Genetic ancestry and diagnostic yield of exome sequencing in a diverse population.","authors":"Yusuph Mavura, Nuriye Sahin-Hodoglugil, Ugur Hodoglugil, Mark Kvale, Pierre-Marie Martin, Jessica Van Ziffle, W Patrick Devine, Sara L Ackerman, Barbara A Koenig, Pui-Yan Kwok, Mary E Norton, Anne Slavotinek, Neil Risch","doi":"10.1038/s41525-023-00385-6","DOIUrl":"10.1038/s41525-023-00385-6","url":null,"abstract":"<p><p>It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"1"},"PeriodicalIF":5.3,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10764913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087811","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
