NPJ Genomic Medicine最新文献

{"title":"An efficient molecular genetic testing strategy for incontinentia pigmenti based on single-tube long fragment read sequencing.","authors":"Min Chen, Mei-Hua Tan, Jiao Liu, Yan-Mei Yang, Jia-Ling Yu, Li-Juan He, Ying-Zhi Huang, Yi-Xi Sun, Ye-Qing Qian, Kai Yan, Min-Yue Dong","doi":"10.1038/s41525-024-00421-z","DOIUrl":"10.1038/s41525-024-00421-z","url":null,"abstract":"<p><p>Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal dysplasia that primarily affects females. The only known causative gene is IKBKG, and the most common genetic cause is the recurrent IKBKG^△4-10 deletion resulting from recombination between two MER67B repeats. Detection of variants in IKBKG is challenging due to the presence of a highly homologous non-pathogenic pseudogene IKBKGP1. In this study, we successfully identified four pathogenic variants in four IP patients using a strategy based on single-tube long fragment read (stLFR) sequencing with a specialized analysis pipeline. Three frameshift variants (c.519-3_519dupCAGG, c.1167dupC, and c.700dupT) were identified and subsequently validated by Sanger sequencing. Notably, c.519-3_519dupCAGG was found in both IKBKG and IKBKGP1, whereas the other two variants were only detected in the functional gene. The IKBKG^△4-10 deletion was identified and confirmed in one patient. These results demonstrate that the proposed strategy can identify potential pathogenic variants and distinguish whether they are derived from IKBKG or its pseudogene. Thus, this strategy can be an efficient genetic testing method for IKBKG. By providing a comprehensive understanding of the whole genome, it may also enable the exploration of other genes potentially associated with IP. Furthermore, the strategy may also provide insights into other diseases with detection challenges due to pseudogenes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"32"},"PeriodicalIF":5.3,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175683","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":"Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.","authors":"Tom Venken, Ian S Miller, Ingrid Arijs, Valentina Thomas, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P Ebert, Alice C O'Farrell, Jochen Prehn, Rut Klinger, Darran P O'Connor, Brian Moulton, Verena Murphy, Garazi Serna, Paolo G Nuciforo, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Diether Lambrechts, Annette T Byrne","doi":"10.1038/s41525-024-00415-x","DOIUrl":"10.1038/s41525-024-00415-x","url":null,"abstract":"<p><p>To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"33"},"PeriodicalIF":5.3,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175684","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":"Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease.","authors":"Blake M Hauser, Yuyang Luo, Anusha Nathan, Ahmad Al-Moujahed, Demetrios G Vavvas, Jason Comander, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Gaurav D Gaiha, Elizabeth J Rossin","doi":"10.1038/s41525-024-00416-w","DOIUrl":"10.1038/s41525-024-00416-w","url":null,"abstract":"<p><p>Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"31"},"PeriodicalIF":4.7,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158960","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":"Evaluating the utility of multi-gene, multi-disease population-based panel testing accounting for uncertainty in penetrance estimates.","authors":"Jane W Liang, Kurt D Christensen, Robert C Green, Peter Kraft","doi":"10.1038/s41525-024-00414-y","DOIUrl":"https://doi.org/10.1038/s41525-024-00414-y","url":null,"abstract":"<p><p>Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities and should account for uncertainties around these factors.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"30"},"PeriodicalIF":5.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958610","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":"Reply to: Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects","authors":"Lonneke Haer-Wigman, Amber den Ouden, Ronny Derks, Maria M. van Genderen, Dorien Lugtenberg, Joke Verheij, Raymon Vijzelaar, Helger G. Yntema, Lisenka E. L. M. Vissers, Kornelia Neveling","doi":"10.1038/s41525-024-00409-9","DOIUrl":"https://doi.org/10.1038/s41525-024-00409-9","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"45 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140839125","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":"Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects","authors":"Bernd Wissinger, Britta Baumann, Elena Buena-Atienza, Caspar Gross, Susanne Kohl","doi":"10.1038/s41525-024-00406-y","DOIUrl":"https://doi.org/10.1038/s41525-024-00406-y","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"53 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838990","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":"Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions","authors":"Ali AlMail, Ahmed Jamjoom, Amy Pan, Min Yi Feng, Vann Chau, Alissa M. D’Gama, Katherine Howell, Nicole S. Y. Liang, Amy McTague, Annapurna Poduri, Kimberly Wiltrout, Anne S. Bassett, John Christodoulou, Lucie Dupuis, Peter Gill, Tess Levy, Paige Siper, Zornitza Stark, Jacob A. S. Vorstman, Catherine Diskin, Natalie Jewitt, Danielle Baribeau, Gregory Costain","doi":"10.1038/s41525-024-00408-w","DOIUrl":"https://doi.org/10.1038/s41525-024-00408-w","url":null,"abstract":"<p>Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in &gt;87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (<i>n</i> = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"68 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591631","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":"Strategies to improve implementation of cascade testing in hereditary cancer syndromes: a systematic review","authors":"Jianbang Chiang, Ziyang Chua, Jia Ying Chan, Ashita Ashish Sule, Wan Hsein Loke, Elaine Lum, Marcus Eng Hock Ong, Nicholas Graves, Joanne Ngeow","doi":"10.1038/s41525-024-00412-0","DOIUrl":"https://doi.org/10.1038/s41525-024-00412-0","url":null,"abstract":"<p>Hereditary cancer syndromes constitute approximately 10% of all cancers. Cascade testing involves testing of at-risk relatives to determine if they carry the familial pathogenic variant. Despite growing efforts targeted at improving cascade testing uptake, current literature continues to reflect poor rates of uptake, typically below 30%. This study aims to systematically review current literature on intervention strategies to improve cascade testing, assess the quality of intervention descriptions and evaluate the implementation outcomes of listed interventions. We searched major databases using keywords and subject heading of “cascade testing”. Interventions proposed in each study were classified according to the Effective Practice and Organization of Care (EPOC) taxonomy. Quality of intervention description was assessed using the TIDieR checklist, and evaluation of implementation outcomes was performed using Proctor’s Implementation Outcomes Framework. Improvements in rates of genetic testing uptake was seen in interventions across the different EPOC taxonomy strategies. The average TIDieR score was 7.3 out of 12. Items least reported include modifications (18.5%), plans to assess fidelity/adherence (7.4%) and actual assessment of fidelity/adherence (7.4%). An average of 2.9 out of 8 aspects of implementation outcomes were examined. The most poorly reported outcomes were cost, fidelity and sustainability, with only 3.7% of studies reporting them. Most interventions have demonstrated success in improving cascade testing uptake. Uptake of cascade testing was highest with delivery arrangement (68%). However, the quality of description of interventions and assessment of implementation outcomes are often suboptimal, hindering their replication and implementation downstream. Therefore, further adoption of standardized guidelines in reporting of interventions and formal assessment of implementation outcomes may help promote translation of these interventions into routine practice.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"165 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591622","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":"Future implications of polygenic risk scores for life insurance underwriting.","authors":"Tatiane Yanes, Jane Tiller, Casey M Haining, Courtney Wallingford, Margaret Otlowski, Louise Keogh, Aideen McInerney-Leo, Paul Lacaze","doi":"10.1038/s41525-024-00407-x","DOIUrl":"10.1038/s41525-024-00407-x","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"25"},"PeriodicalIF":5.3,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10981684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140330041","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":"Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib.","authors":"K M Ingley, M Zatzman, A M Fontebasso, W Lo, V Subasri, A Goldenberg, Y Li, S Davidson, N Kanwar, L Waldman, L Brunga, Y Babichev, E G Demicco, A Gupta, M Szybowska, S Thipphavong, D Malkin, A Villani, A Shlien, R A Gladdy, R H Kim","doi":"10.1038/s41525-024-00405-z","DOIUrl":"10.1038/s41525-024-00405-z","url":null,"abstract":"<p><p>Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"24"},"PeriodicalIF":5.3,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10973472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306358","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}