Genetics in Medicine最新文献

{"title":"A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort","authors":"Sarah Fazal ,&nbsp;Harriet Dashnow ,&nbsp;Maike F. Dohrn ,&nbsp;Jacquelyn Raposo ,&nbsp;Laurel Hiatt ,&nbsp;Matt C. Danzi ,&nbsp;Isaac R.L. Xu ,&nbsp;Camilo Toro ,&nbsp;David R. Adams ,&nbsp;Karen Usdin ,&nbsp;Bruce Hayward ,&nbsp;Shilpa Nadimpalli Kobren ,&nbsp;Shamil R. Sunyaev ,&nbsp;Rebecca C. Spillmann ,&nbsp;Vandana Shashi ,&nbsp;Adriana Rebelo ,&nbsp;Guney Bademci","doi":"10.1016/j.gim.2025.101462","DOIUrl":"10.1016/j.gim.2025.101462","url":null,"abstract":"<div><h3>Purpose</h3><div>The Undiagnosed Diseases Network is a National Institutes of Health funded research study that aims to solve a broad clinical spectrum of challenging rare disease cases. Participants receive care from multiple clinical specialists, who collaborate to perform deep phenotyping and state-of-the-art multiomics analyses. As bioinformatics of short-read sequencing has matured, the discovery of repeat expansion disorders (REDs) is accelerating. REDs comprise approximately 60 characterized disorders, which exhibit a broad spectrum of phenotypes. Thus, a largely unbiased genome-wide approach in a phenotypically diverse sample will add to the diagnostic depth, explore the limits of short-read genome analysis, and establish novel candidate RED loci.</div></div><div><h3>Methods</h3><div>Here, we present a genome-wide analysis of repeat expansions conducted on 1018 genomes from the Undiagnosed Diseases Network. By leveraging 2 distinct bioinformatics tools, ExpansionHunter Denovo and STRling, we showed that repeat expansions can be accurately detected in short-read genomes.</div></div><div><h3>Results</h3><div>We demonstrated that a genotype-first approach can diagnose atypical cases of known REDs and provide valuable clinical insights. We present clinical details on participants with expansions in <em>ATXN7</em>, <em>DMPK</em>, <em>FMR1</em>, <em>GLS</em>, <em>HTT</em>, <em>RFC1</em>, <em>AFF3</em>, and <em>MARCH6</em>. Importantly, we highlight 2 cases of juvenile Huntington disease that were discovered through our analysis. Finally, we present a list of novel candidate short tandem repeats (TR) that could potentially be pathogenic if expanded.</div></div><div><h3>Conclusion</h3><div>Importantly, our approach showcases the bioinformatic advancements in genome analysis for RED detection and highlights its practical applications.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101462"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cost-utility of targeted germline BRCA testing in localized prostate cancer followed by cascade testing first-degree relatives with pathogenic variants","authors":"Srinivas Teppala ,&nbsp;Paul Scuffham ,&nbsp;Kim Edmunds ,&nbsp;Matthew J. Roberts ,&nbsp;David P. Smith ,&nbsp;David Fairbairn ,&nbsp;Lisa G. Horvath ,&nbsp;Haitham Tuffaha","doi":"10.1016/j.gim.2025.101463","DOIUrl":"10.1016/j.gim.2025.101463","url":null,"abstract":"<div><h3>Purpose</h3><div>Genetic testing is recommended in localized prostate cancer (PCa) with elevated risk and in metastatic PCa. The economics of genetic testing in metastatic PCa has been evaluated but not assessed in localized PCa. We examined the cost utility of germline <em>BRCA</em> testing in localized PCa with high risk of pathogenic variants.</div></div><div><h3>Methods</h3><div>Cost-utility analysis of germline <em>BRCA</em> testing in localized PCa with (1) high/very high-risk classification, (2) family history of PCa, and (3) Ashkenazi-Jewish ancestry. Analyses were performed from an Australian payer perspective using semi-Markov models over lifetime; quality-adjusted life years (QALYs) were the health outcomes. Decision uncertainty was characterized using 1-way and probabilistic sensitivity analyses.</div></div><div><h3>Results</h3><div>The incremental cost-effectiveness ratio of <em>BRCA</em> testing compared with no testing was AU$591,408/QALY in patients with high/very high risk, AU$3.9 million/QALY with family history of PCa, and AU$650,098/QALY in Ashkenazi-Jews. Adding cascade testing of first-degree relatives (FDRs) resulted in incremental cost-effectiveness ratios of AU$18,872/QALY, AU$47,294/QALY, and AU$14,637/QALY in the aforementioned groups. At a willingness-to-pay of AU$75,000/QALY, <em>BRCA</em> testing was not likely to be cost-effective in PCa patients; however, it was cost-effective after cascade testing FDRs.</div></div><div><h3>Conclusion</h3><div>Germline <em>BRCA</em> testing may not be cost-effective when limited to patients with localized PCa but demonstrates value for money when extended to FDRs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101463"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: A phase-3, 2-part study compared with a historical placebo cohort","authors":"Young Bae Sohn ,&nbsp;Aram Yang ,&nbsp;Min-Sun Kim ,&nbsp;Jinsup Kim ,&nbsp;Jae Seong Kim ,&nbsp;Youngsin Oh ,&nbsp;Dong-Kyu Jin","doi":"10.1016/j.gim.2025.101460","DOIUrl":"10.1016/j.gim.2025.101460","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the efficacy and safety of idursulfase beta (0.5 mg/kg weekly) in the treatment of mucopolysaccharidosis II, compared with a historical placebo from a previous idursulfase trial (TKT024).</div></div><div><h3>Methods</h3><div>The study comprised 2 sequential parts. In part 1, a randomized, double-blind study, idursulfase or idursulfase beta were given for 52 weeks. In the open, single-cohort part 2 study, additional participants received idursulfase beta for 52 weeks. Data from the idursulfase beta groups from parts 1 and 2 were pooled for comparisons with the historical placebo group (<em>n</em> = 32). The primary end point was a change in the 6-minute walk test at week 53.</div></div><div><h3>Results</h3><div>Participants in the idursulfase beta groups (<em>n</em> = 24) were male Asians (mean age, 12.0 years). Idursulfase beta was superior to placebo in 6-minute walk test improvement (62.2 vs 7.3 m, <em>P &lt;</em> .0001). Decrease in urine glycosaminoglycan excretion (−71.13% vs 21.39%, <em>P &lt;</em> .0001) and reduction in the liver (−26.67% vs −0.80%, <em>P &lt;</em> .0001) and spleen volumes (−26.46% vs 7.2%, <em>P &lt;</em> .0001) were significant. The safety profile of idursulfase beta was satisfactory.</div></div><div><h3>Conclusion</h3><div>Idursulfase beta is a safe and effective treatment option in mucopolysaccharidosis II, addressing crucial somatic ailments presented by patients.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101460"},"PeriodicalIF":6.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustainability in translational genomics research with undiagnosed patients: What is it, why do we need it, and how do we do it?","authors":"Jennifer L. Young ,&nbsp;Charis Tang ,&nbsp;Lily Liang ,&nbsp;Euan A. Ashley ,&nbsp;Holly K. Tabor ,&nbsp;Meghan C. Halley","doi":"10.1016/j.gim.2025.101458","DOIUrl":"10.1016/j.gim.2025.101458","url":null,"abstract":"<div><h3>Purpose</h3><div>Genomics research enrolling undiagnosed patients can provide answers for one-third of participants, and more can be diagnosed through future reanalysis. The long-term value for participants has raised questions of the sustainability of these studies, but the meaning, goals, and best practices for sustainability remain unclear.</div></div><div><h3>Methods</h3><div>We conducted semistructured interviews with researchers leading studies enrolling undiagnosed patients in the United States and Canada and used thematic content analysis to summarize key themes.</div></div><div><h3>Results</h3><div>Researchers lacked consensus regarding what sustainability was actually intended to sustain, variably referencing study procedures, personnel, data access, and participant recontact. However, the primary driver of sustainability was widely shared as the perceived obligation to continue to search for answers for undiagnosed participants. Proposed sustainability strategies included diversifying funding sources, developing centralized data infrastructure, and building collaborations across disciplines and institutions. Researchers also emphasized the need to address ethical concerns, to integrate research with clinical care, and for leadership from research funders to guide these efforts.</div></div><div><h3>Conclusion</h3><div>Although genomics researchers perceived continued obligations to undiagnosed participants, they also lacked a shared understanding of the goals of sustainability and called for coordinated efforts to develop centralized infrastructure that integrated research and clinical care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101458"},"PeriodicalIF":6.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term management strategies for pegvaliase use in phenylketonuria: Lessons learned from the phase-3 PRISM open-label extension study","authors":"Cary O. Harding ,&nbsp;Kaleigh Bulloch Whitehall ,&nbsp;Joshua Lilienstein ,&nbsp;Ogun Sazova ,&nbsp;Kristin Lindstrom ,&nbsp;Drew G. Levy ,&nbsp;Barbara K. Burton","doi":"10.1016/j.gim.2025.101459","DOIUrl":"10.1016/j.gim.2025.101459","url":null,"abstract":"<div><h3>Purpose</h3><div>Pegvaliase is an enzyme substitution therapy for phenylketonuria, an autosomal recessive disorder of amino acid metabolism resulting in phenylalanine (Phe) accumulation, intellectual disability, and behavioral/psychiatric disorders. The phase-3 PRISM trials (NCT01819727, NCT01889862, and NCT03694353) established pegvaliase efficacy in reducing blood Phe, but its pharmacokinetics differs between individuals, resulting in varying times to achieve clinically meaningful blood Phe targets.</div></div><div><h3>Methods</h3><div>Using participant-level data from PRISM, we developed a pharmacokinetic/pharmacodynamic model that explains individual-level blood Phe patterns as a function of pegvaliase clearance during the maintenance phase.</div></div><div><h3>Results</h3><div>As pegvaliase exposure induces immune tolerization, drug clearance declines. A period of high sensitivity of blood Phe to dietary Phe intake and pegvaliase exposure is observed at ∼120 to 200 μmol/L Phe, reflected in increased blood Phe volatility. This model suggests that this volatility represents impending, but incomplete, tolerization and that reducing pegvaliase dose or liberalizing dietary Phe intake at or before this stage is premature and can result in marked blood Phe increases. With continued exposure, pegvaliase clearance continues to decline, and dietary Phe intake and blood Phe become uncoupled.</div></div><div><h3>Conclusion</h3><div>These analyses establish how tolerization presents clinically and suggest a staged therapeutic approach: (1) tolerance induction, (2) diet liberalization, and (3) gradual dose adjustment.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101459"},"PeriodicalIF":6.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covering medical care costs for participants in the eMERGE Network: Challenges for equity and implementation","authors":"Laura J. Rasmussen-Torvik ,&nbsp;Katherine E. Bonini ,&nbsp;Margaret H. Harr ,&nbsp;Mohammad Ali Abbass ,&nbsp;Hana Bangash ,&nbsp;Harris T. Bland ,&nbsp;Brenna M. Boyd ,&nbsp;Wendy K. Chung ,&nbsp;Ellen W. Clayton ,&nbsp;Stuart J. Cohen ,&nbsp;John J. Connolly ,&nbsp;Catherine Gascoigne ,&nbsp;Valentina Hernandez ,&nbsp;Ingrid A. Holm ,&nbsp;Martha Horike-Pyne ,&nbsp;Gail P. Jarvik ,&nbsp;Elizabeth W. Karlson ,&nbsp;Iftikhar J. Kullo ,&nbsp;Nita A. Limdi ,&nbsp;Mary E. Maradik ,&nbsp;Maya Sabatello","doi":"10.1016/j.gim.2025.101457","DOIUrl":"10.1016/j.gim.2025.101457","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the complexities of covering study-recommended medical care costs for individuals (in order to prevent lack of adherence due to financial reasons), which have received little attention.</div></div><div><h3>Methods</h3><div>We explored the deliberations, decisions, and challenges faced by the Electronic Medical Records and Genomics (eMERGE) Network during the implementation of a genomic research project recommending clinical care based on high-risk results defined largely by polygenic risk scores. Two surveys were disseminated to eMERGE sites: to identify preferences about payment for specific care recommendations (survey 1) and to understand the operational processes of covering medical care costs (survey 2).</div></div><div><h3>Results</h3><div>Paying for a subset of care recommendations for the funded study duration was identified as the most feasible approach for covering medical care costs for participants who received high-risk genomic results. Each eMERGE site, by necessity, used diverse approaches to pay for medical care costs.</div></div><div><h3>Conclusion</h3><div>eMERGE researchers balanced competing concerns about bias, equity, study design, regulatory compliance, and cost in designing a unified approach to cover some of the recommended medical care costs in the study. Many implementation challenges were encountered. Findings can inform researchers and regulatory bodies about the implications and complications of covering medical care costs in translational research studies focused on prevention.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101457"},"PeriodicalIF":6.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial","authors":"Can Ficicioglu ,&nbsp;Janet A. Thomas ,&nbsp;Jaya Ganesh ,&nbsp;David Kudrow ,&nbsp;Melissa Lah ,&nbsp;Wendy E. Smith ,&nbsp;Jalé Güner ,&nbsp;Sharon McDermott ,&nbsp;Sagar A. Vaidya ,&nbsp;Liz Wilkening ,&nbsp;Harvey L. Levy","doi":"10.1016/j.gim.2025.101456","DOIUrl":"10.1016/j.gim.2025.101456","url":null,"abstract":"<div><h3>Purpose</h3><div>Because the standard-of-care treatment for classical homocystinuria (HCU) often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy.</div></div><div><h3>Methods</h3><div>Participants with HCU aged 12 to 65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into 6 increasing dose cohorts (each <em>n</em> ≈ 4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to posttreatment (geometric mean of weeks 6-12).</div></div><div><h3>Results</h3><div>Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; 1 serious [acute urticaria]). At the 2 highest doses, substantial tHcy reductions were observed after treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW), and all participants maintained tHcy &lt; 100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy &lt; 15 μM (normal) and methionine &lt; 14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy.</div></div><div><h3>Conclusion</h3><div>Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101456"},"PeriodicalIF":6.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking agency for genetic testing intention among Latinos: Determining predictors of intention for carrier screening and cancer predisposition testing","authors":"Daniel Chavez-Yenter ,&nbsp;Kimberly A. Kaphingst","doi":"10.1016/j.gim.2025.101455","DOIUrl":"10.1016/j.gim.2025.101455","url":null,"abstract":"<div><h3>Purpose</h3><div>Attitudes and clinical processes have been well studied in genetic testing contexts; however, studies tend to underutilize theoretical frameworks, especially among Latino groups. Behavioral intention is a consistent predictor of uptake of behavior and has many theoretical roots. Using the Integrated Behavioral Model, we modeled the relationships between attitudes, norms, and perceived agency with behavioral intention for both carrier screening (CS) and cancer predisposition testing (CPT) for a Latino-only cohort.</div></div><div><h3>Methods</h3><div>Using structural equation modeling, we ran both measurement and structural models. An initial measurement model used confirmatory factor analysis for each latent variable (attitude, norms, and agency) and their indicators of the Integrated Behavioral Model. Factor loadings less than 0.50 were removed, and we subsequently ran a structural model with the outcome of intention to use CS and CPT.</div></div><div><h3>Results</h3><div>Agency was the most consistent predictor for both testing types (b = 0.381, <em>P</em> &lt; .01 − CS; b = 0.559, <em>P</em> &lt; .01 − CPT), with attitudes being negatively associated with CS (b = −0.313, <em>P</em> &lt; .05), whereas norms were positively associated (b = 0.350, <em>P</em> &lt; .01).</div></div><div><h3>Conclusion</h3><div>Many interventions among Latino groups tend to focus on education and attitude change. Our findings suggest that more effort should be made to address agency to empower patients for improved genetic testing access.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101455"},"PeriodicalIF":6.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychological and emotional impacts of communicating breast cancer risk using multifactorial assessment with polygenic risk score: Findings from PERSPECTIVE I&I","authors":"Laurence Lambert-Côté ,&nbsp;Annie Turgeon ,&nbsp;Kristina M. Blackmore ,&nbsp;Amy Chang ,&nbsp;Antonis C. Antoniou ,&nbsp;Kathleen A. Bell ,&nbsp;Mireille J.M. Broeders ,&nbsp;Jennifer D. Brooks ,&nbsp;Tim Carver ,&nbsp;Sue-Ling Chang ,&nbsp;Jocelyne Chiquette ,&nbsp;Éric Demers ,&nbsp;Douglas F. Easton ,&nbsp;Andrea Eisen ,&nbsp;Laurence Eloy ,&nbsp;D. Gareth R. Evans ,&nbsp;Samantha Fienberg ,&nbsp;Yann Joly ,&nbsp;Raymond H. Kim ,&nbsp;Bartha M. Knoppers ,&nbsp;Michel Dorval","doi":"10.1016/j.gim.2025.101453","DOIUrl":"10.1016/j.gim.2025.101453","url":null,"abstract":"<div><h3>Purpose</h3><div>To examine the psychological and emotional outcomes of personalized breast cancer risk communication up to 1 year after disclosure in a risk-stratified breast screening preimplementation study (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation).</div></div><div><h3>Methods</h3><div>Among 3753 females aged 40 to 69, unaffected by breast cancer, with a prior mammogram, and who underwent multifactorial risk assessment to estimate their 10-year breast cancer risk, 2734 completed follow-up questionnaires up to 1 year after risk communication: 78.5% were at average risk, 16.5% at higher than average risk, and 5.0% at high risk. The impact of risk communication on breast cancer worry and psychological distress and factors associated with decisional regret were examined.</div></div><div><h3>Results</h3><div>Breast cancer worry and psychological distress scores remained low after risk communication and at 1 year follow-up. Up to 1 year after disclosure, small significant differences in breast cancer worry were observed between risk levels. Decisional regret was very low 1 year after risk communication. Lower levels of decisional regret were significantly associated with some factors, including higher satisfaction with the information received.</div></div><div><h3>Conclusion</h3><div>This study suggests that personalized breast cancer risk communication has low negative psychological and emotional effects and highlights the importance of the information received for implementing this approach at population level.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101453"},"PeriodicalIF":6.6,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven consideration of genetic disorders for global genomic newborn screening programs","authors":"Thomas Minten ,&nbsp;Sarah Bick ,&nbsp;Sophia Adelson ,&nbsp;Nils Gehlenborg ,&nbsp;Laura M. Amendola ,&nbsp;François Boemer ,&nbsp;Alison J. Coffey ,&nbsp;Nicolas Encina ,&nbsp;Alessandra Ferlini ,&nbsp;Janbernd Kirschner ,&nbsp;Bianca E. Russell ,&nbsp;Laurent Servais ,&nbsp;Kristen L. Sund ,&nbsp;Ryan J. Taft ,&nbsp;Petros Tsipouras ,&nbsp;Hana Zouk","doi":"10.1016/j.gim.2025.101443","DOIUrl":"10.1016/j.gim.2025.101443","url":null,"abstract":"<div><h3>Purpose</h3><div>Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes.</div></div><div><h3>Methods</h3><div>We assembled a data set comprising 25 characteristics about each of the 4390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion and developed a machine learning model to rank genes for public health consideration.</div></div><div><h3>Results</h3><div>Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%), and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (area under the curve = 0.915, R² = 84%).</div></div><div><h3>Conclusion</h3><div>The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101443"},"PeriodicalIF":6.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}