Genetics in Medicine最新文献

{"title":"Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications","authors":"Sarah C. Grünert ,&nbsp;Matthias R. Baumgartner ,&nbsp;Juliette Bouchereau ,&nbsp;Alberto Burlina ,&nbsp;Peter T. Clayton ,&nbsp;Javier de las Heras ,&nbsp;Carlo Dionisi-Vici ,&nbsp;Corinne Gemperle-Britschgi ,&nbsp;Claudia Haase ,&nbsp;Stanley H. Korman ,&nbsp;Johannes Krämer ,&nbsp;Eva Kühlwein ,&nbsp;Esther M. Maier ,&nbsp;Arianna Maiorana ,&nbsp;Manuel Schiff ,&nbsp;Carl Ulrich Schmid ,&nbsp;Trine Tangeraas ,&nbsp;Raina Yamamoto ,&nbsp;Johannes Zschocke ,&nbsp;Jörn Oliver Sass","doi":"10.1016/j.gim.2025.101484","DOIUrl":"10.1016/j.gim.2025.101484","url":null,"abstract":"<div><h3>Purpose</h3><div>Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in <em>HMGCS2</em>. Only 59 patients with this disorder have been reported so far.</div></div><div><h3>Methods</h3><div>We performed a comprehensive literature search to identify all published cases of HMGCS2D (<em>n</em> = 59). Additionally, the data of 16 patients with this disorder who are yet undescribed were collected. Clinical course, biochemical findings, and mutation data are highlighted and discussed. An overview on all <em>HMGCS2</em> variants reported in patients is provided.</div></div><div><h3>Results</h3><div>Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only 1 variant was identified to be common, (<em>HMGCS2</em>) NM_005518.4:c.634G&gt;A p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established.</div></div><div><h3>Conclusion</h3><div>This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D, including a list of <em>HMGCS2</em> variants identified in affected individuals.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101484"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293630","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":"Optimizing participant and community engagement in cancer genomic sequencing research","authors":"Norah L. Crossnohere ,&nbsp;Anne L.R. Schuster ,&nbsp;Cindy K. Blair ,&nbsp;Hasani Bland ,&nbsp;John D. Carpten ,&nbsp;Elizabeth B. Claus ,&nbsp;Graham A. Colditz ,&nbsp;Diane Diehl ,&nbsp;Li Ding ,&nbsp;Bettina F. Drake ,&nbsp;Ryan C. Fields ,&nbsp;Suzanne George ,&nbsp;Katherine Janeway ,&nbsp;Hyoshin Kim ,&nbsp;Heinz-Josef Lenz ,&nbsp;Jennifer W. Mack ,&nbsp;Charité Ricker ,&nbsp;Mariana C. Stern ,&nbsp;Andrew Sussman ,&nbsp;Jeffrey Trent ,&nbsp;Zachary Crees","doi":"10.1016/j.gim.2025.101483","DOIUrl":"10.1016/j.gim.2025.101483","url":null,"abstract":"<div><h3>Purpose</h3><div>We describe strategies implemented across research centers of the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network to optimize engagement of participants and communities in cancer genomics research. We also present consensus definitions of engagement and engagement optimization, informed by our shared experiences in the Network.</div></div><div><h3>Methods</h3><div>Key informant interviews and a document review identified engagement and optimization strategies across PE-CGS research centers. Findings were synthesized using qualitative content analysis. Consensus on definitions of engagement and optimization were developed through iterative review by PE-CGS members.</div></div><div><h3>Results</h3><div>PE-CGS research centers adopted tailored strategies based on community needs and scientific gaps. Engagement strategies included community-based efforts (eg, advisory boards and newsletters) and participant-focused approaches (eg, enhanced informed consent and decision support tools). Optimization strategies leveraged scientific methods (eg, randomized controlled trials and surveys) to evaluate engagement. Engagement was described as the sustained and meaningful interactions between researchers, participants, and communities. Optimization was described as the application of scientific methods to refine and improve engagement and research processes and outcomes.</div></div><div><h3>Conclusion</h3><div>Engagement and optimization strategies have informed research planning, conduct, and dissemination across PE-CGS. These approaches and definitions provide a foundation for developing evidence-based practices to strengthen participant and community involvement in cancer genomics research.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101483"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301930","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":"Costs and cost-effectiveness of returning secondary findings from genomic sequencing based on the return of additional findings in the 100,000 Genomes Project","authors":"Emma J. Smith ,&nbsp;Melissa Hill ,&nbsp;Lyn S. Chitty ,&nbsp;Stephen Morris","doi":"10.1016/j.gim.2025.101479","DOIUrl":"10.1016/j.gim.2025.101479","url":null,"abstract":"<div><h3>Purpose</h3><div>To assess costs and cost-effectiveness of returning additional findings from genome sequencing using data from the 100,000 Genomes Project (100kGP).</div></div><div><h3>Methods</h3><div>A model-based cost-utility analysis combining yield, consent rates, and cost data from the 100kGP with published estimates of downstream costs and quality-adjusted life years expected to accrue over a lifetime, after the identification of a pathogenic variant.</div></div><div><h3>Results</h3><div>The cost of returning additional findings to participants in the 100kGP was £7.1m or £81 per participant, with a yield of 0.85% for consented participants. The estimated lifetime incremental cost per participant was £125 and quality-adjusted life years 0.004, giving an incremental cost-effectiveness ratio of £28,830. Implementing a policy of returning additional findings is unlikely to be cost-effective (ie, 13%) at a willingness-to-pay threshold of £20,000. A short-term cost of returning findings of £43 per participant or lower (compared with the base case of £81) would result in an incremental cost-effectiveness ratio of less than £20,000. Alternatively, cost-effectiveness may be improved by returning additional findings to younger patient populations.</div></div><div><h3>Conclusion</h3><div>Return of additional findings following genome sequencing for this group of conditions may not be a cost-effective use of health care system resources. Our cost-effectiveness outcomes rely on published estimates and should be validated through long-term follow-up data.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101479"},"PeriodicalIF":6.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247484","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":"Wilms tumor characteristics in children with heterozygous germline DIS3L2 variants","authors":"S.E. van Peer ,&nbsp;T.D. Treger ,&nbsp;J. Wegert ,&nbsp;J.A. Hol ,&nbsp;J. Le Gall ,&nbsp;E.E. Jakkula ,&nbsp;J. Kamihara ,&nbsp;E.A. Mullen ,&nbsp;N. Graf ,&nbsp;S. Behjati ,&nbsp;R. Al-Saadi ,&nbsp;C. Duncan ,&nbsp;J. Schienda ,&nbsp;R. de Putter ,&nbsp;J. Brzezinski ,&nbsp;A. Verschuur ,&nbsp;O. Michaeli ,&nbsp;M.V. Ortiz ,&nbsp;J.C. Herkert ,&nbsp;R. Armstrong ,&nbsp;M.C.J. Jongmans","doi":"10.1016/j.gim.2025.101478","DOIUrl":"10.1016/j.gim.2025.101478","url":null,"abstract":"<div><h3>Purpose</h3><div>Heterozygous germline <em>DIS3L2</em> pathogenic variants were recently linked to Wilms tumor (WT) predisposition. Limited data on cancer penetrance and characteristics complicate surveillance/management recommendations. This study aims to describe an extended cohort of children with WTs and heterozygous germline <em>DIS3L2</em> (likely) pathogenic variants ([L]PVs).</div></div><div><h3>Methods</h3><div>Clinical and tumor data of children with WT and heterozygous germline <em>DIS3L2</em> (L)PVs were retrospectively collected.</div></div><div><h3>Results</h3><div>Thirty-four children were identified, including 4 familial cases. Germline (L)PVs included exon 9 deletions (<em>n</em> = 28) and other (<em>n</em> = 6) (L)PVs. Seventeen parents were confirmed to have the <em>DIS3L2</em> (L)PV, of whom 1 had a past WT. Median age at WT diagnosis was 41 months (range: 8-101). A somatic second hit in <em>DIS3L2</em> was found in 19 of 20 children with genetic tumor data. Five children had bilateral WTs and 11 had metastases (32%). Eight children had high-risk tumor histology (24%, of which 7 post-chemotherapy blastemal). Three children relapsed or developed a second primary tumor; 4 children were deceased. Recurring clinical features were lacking.</div></div><div><h3>Conclusion</h3><div>Children with WTs and heterozygous germline <em>DIS3L2</em> (L)PVs lack a recognizable phenotype. <em>DIS3L2</em> (L)PVs are a cause for familial WT, but WT penetrance is likely low. This cohort exhibits a high percentage of metastases and high-risk blastemal tumors, which need further study.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101478"},"PeriodicalIF":6.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247485","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":"Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome","authors":"Susan Walker ,&nbsp;David J. Bunyan ,&nbsp;Huw B. Thomas ,&nbsp;Yesim Kesim ,&nbsp;Christopher J. Kershaw ,&nbsp;John Holloway ,&nbsp;Htoo Wai ,&nbsp;Michael Day ,&nbsp;Cassandra L. Smith ,&nbsp;Gareth Hawkes ,&nbsp;Andrew R. Wood ,&nbsp;Michael N. Weedon ,&nbsp;Ed Blair ,&nbsp;Stephanie L. Curtis ,&nbsp;Catherine Fielden ,&nbsp;Julie Evans ,&nbsp;Rebecca Whittington ,&nbsp;Sarah F. Smithson ,&nbsp;Helen Cox ,&nbsp;Paul Clift ,&nbsp;Alistair T. Pagnamenta","doi":"10.1016/j.gim.2025.101477","DOIUrl":"10.1016/j.gim.2025.101477","url":null,"abstract":"<div><h3>Purpose</h3><div>To quantify the impact of noncanonical <em>FBN1</em> splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD).</div></div><div><h3>Methods</h3><div>A systematic analysis of ultrarare <em>FBN1</em> variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank.</div></div><div><h3>Results</h3><div>Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in <em>FBN1</em> of which 21 were predicted to affect splicing (SpliceAI &gt; 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, <em>P =</em> 9.7 × 10⁻¹⁴). Additional analysis uncovered a further 14 families harboring 11 different <em>FBN1</em> splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101477"},"PeriodicalIF":6.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233826","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":"A primer on regulation of laboratory-developed testing procedures: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Marco L. Leung ,&nbsp;Raymond C. Caylor ,&nbsp;Olivia D’Annibale ,&nbsp;Michelle McClure ,&nbsp;TaraChandra Narumanchi ,&nbsp;Laura M. Sack ,&nbsp;Sarah T. South ,&nbsp;ACMG Advocacy and Government Affairs Committee","doi":"10.1016/j.gim.2025.101391","DOIUrl":"10.1016/j.gim.2025.101391","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101391"},"PeriodicalIF":6.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983945","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 risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)","authors":"Linda A.J. Hendricks ,&nbsp;Katja C.J. Verbeek ,&nbsp;Janneke H.M. Schuurs-Hoeijmakers ,&nbsp;Mirjam M. de Jong ,&nbsp;Thera P. Links ,&nbsp;Hilde Brems ,&nbsp;Mio Aerden ,&nbsp;Joan Brunet ,&nbsp;Roser Lleuger-Pujol ,&nbsp;Robert Hüneburg ,&nbsp;Stefan Aretz ,&nbsp;Chrystelle Colas ,&nbsp;Marie-Charlotte Villy ,&nbsp;Emma R. Woodward ,&nbsp;D. Gareth Evans ,&nbsp;Daniëlle G.M. Bosch ,&nbsp;Stephany H. Donze ,&nbsp;Lenka Foretová ,&nbsp;Ana Blatnik ,&nbsp;Edward M. Leter ,&nbsp;Janet R. Vos","doi":"10.1016/j.gim.2025.101467","DOIUrl":"10.1016/j.gim.2025.101467","url":null,"abstract":"<div><h3>Purpose</h3><div>Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk.</div></div><div><h3>Methods</h3><div>This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires.</div></div><div><h3>Results</h3><div>Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively.</div></div><div><h3>Conclusion</h3><div>This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101467"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144158225","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 2023 medical genetics workforce in the United States","authors":"Megan Lyon ,&nbsp;Deborah Maiese ,&nbsp;Miriam G. Blitzer ,&nbsp;Rhonda West ,&nbsp;Vivian Pan ,&nbsp;Cinthya Zepeda Mendoza ,&nbsp;Laurie M. Connors ,&nbsp;Beth Ogata ,&nbsp;Erin MacLeod ,&nbsp;Nguyen Park ,&nbsp;Marci K. Sontag ,&nbsp;Molly Caisse ,&nbsp;Mathew J. Edick ,&nbsp;Sylvia Mann ,&nbsp;Kunal Sanghavi ,&nbsp;Joann Bodurtha","doi":"10.1016/j.gim.2025.101461","DOIUrl":"10.1016/j.gim.2025.101461","url":null,"abstract":"<div><h3>Purpose</h3><div>To characterize the 2023 medical genetics and genomics workforce in the United States—comprising clinical geneticists, genetic counselors, genetic nurses, genetic physician assistants, laboratory geneticists, and metabolic dietitians—to inform genetics workforce efforts.</div></div><div><h3>Methods</h3><div>National genetics membership or board-certification organizations distributed an electronic survey to medical genetics professionals in early 2023. Questions were derived from prior workforce surveys and by a workgroup led by the National Coordinating Center for the Regional Genetics Networks.</div></div><div><h3>Results</h3><div>Of the 3070 medical genetics professionals who responded, 66.0% were genetic counselors, 15.4% were clinical geneticists, 12.2% were laboratory geneticists, 4.7% were metabolic dietitians, and 1.7% were genetic nurses or physician assistants. The respondents identified as White (76.1%) and women (84.7%); there were statistically significant differences between disciplines. Forty percent worked in academic centers; 55.3% worked 41+ hours per week. Nearly 11% of respondents provided services in a language other than English. Despite 34.7% of respondents experiencing some burnout, most had no plans to leave the field (94.4%) within the next year.</div></div><div><h3>Conclusion</h3><div>The medical genetics community needs to advance workforce initiatives to support current personnel and attract new and diverse individuals to the field to serve patients and their families.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101461"},"PeriodicalIF":6.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208414","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":"Mainstreaming of clinical genetic testing: A conceptual framework","authors":"Michael P. Mackley ,&nbsp;Julie Richer ,&nbsp;Andrea Guerin ,&nbsp;Oana Caluseriu ,&nbsp;Linlea Armstrong ,&nbsp;Katherine A. Blood ,&nbsp;Francois Bernier ,&nbsp;Christie Boswell-Patterson ,&nbsp;Marisa Chard ,&nbsp;Gregory Costain ,&nbsp;David Dyment ,&nbsp;Alison Eaton ,&nbsp;Hanna Faghfoury ,&nbsp;Patrick Frosk ,&nbsp;Meredith K. Gillespie ,&nbsp;Elaine S. Goh ,&nbsp;Robin Z. Hayeems ,&nbsp;Bita Hashemi ,&nbsp;A. Micheil Innes ,&nbsp;Molly Jackson ,&nbsp;Kym M. Boycott","doi":"10.1016/j.gim.2025.101465","DOIUrl":"10.1016/j.gim.2025.101465","url":null,"abstract":"<div><h3>Purpose</h3><div>Demand for genetic testing is increasing across medicine, whereas the genetics workforce remains stable. In response, mainstreaming models are being introduced, in which nongeneticist clinicians are increasingly involved in the genetic testing pathway. Because a standardized approach would facilitate evaluation and optimal patient care, a unified framework is warranted.</div></div><div><h3>Methods</h3><div>Through a focus group with clinical genetics experts, a conceptual framework for the mainstreaming of clinical genetic testing is proposed. Through a consensus process, experts elucidated the steps in the diagnostic care pathway and defined a set of variables that influence which mainstreaming model is best suited to specific patient care scenarios.</div></div><div><h3>Results</h3><div>A total of 35 individuals representing 20 distinct clinical genetics services and all Canadian provinces participated in the development of the framework. The framework describes 4 generalizable mainstreaming models of care, each with varying levels of involvement of the clinical genetics service in the diagnostic care pathway.</div></div><div><h3>Conclusion</h3><div>This framework will help guide clinical teams in the design and evaluation of mainstreaming efforts. It is critical that these programs are evaluated and shared in a standardized way so that we can implement strategies that allow optimal utilization of genetics resources and improve patient care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101465"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142310","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":"Impact of laboratory-driven proactive reanalysis: Reclassification to positive in 5% of initially negative or uncertain exome sequencing cases","authors":"Meghan C. Towne ,&nbsp;Jennifer Huang ,&nbsp;Sheila Saliganan ,&nbsp;Brooklynn Gasser ,&nbsp;Melissa Holman ,&nbsp;Kendra Webb ,&nbsp;Bess Wayburn ,&nbsp;Kelly Radtke ,&nbsp;Kelly D. Farwell Hagman","doi":"10.1016/j.gim.2025.101464","DOIUrl":"10.1016/j.gim.2025.101464","url":null,"abstract":"<div><h3>Purpose</h3><div>Reanalysis of exome sequencing (ES) data increases diagnostic utility; however, there is no consensus on when and under what circumstances reanalysis should occur. Requesting and performing ES reanalysis burdens both clinical and laboratory workflows. Maximizing the potential for reclassification is essential. Here, we describe the impact of a laboratory-driven proactive reanalysis process that triggers reanalysis when new evidence is identified.</div></div><div><h3>Methods</h3><div>We reviewed reanalysis outcomes of an ES cohort. Reanalysis events were categorized based on initiating factors (laboratory-driven proactive, family studies, and clinician-initiated). Laboratory-driven proactive reclassifications are prompted by systematic review of new scientific data. Outcomes were evaluated by initiating factors, reclassification types, evidence used, and time since original report.</div></div><div><h3>Results</h3><div>Overall, 23% of cases underwent at least 1 reanalysis, with 35% of reanalyses resulting in reclassification. There was a 4% increase in diagnostic yield, including 5% of initially unsolved ES receiving diagnostic reports. Diagnostic reclassifications rates were significantly higher for laboratory-driven proactive reanalyses (54%; <em>P</em> &lt; .0001) than family studies (18%) and clinician-initiated reanalyses (4%). New gene-disease relationships were the most efficacious evidence source. Laboratory-driven proactive reclassifications occurred steadily over time.</div></div><div><h3>Conclusion</h3><div>Laboratory-driven proactive reanalysis effectively provides more diagnostic reclassifications compared with clinician-initiated reanalysis. Laboratories should curate and integrate emerging evidence into ES reanalysis.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101464"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142307","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}