Genetics in Medicine最新文献

{"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, Annie Turgeon, Kristina M Blackmore, Amy Chang, Antonis C Antoniou, Kathleen A Bell, Mireille J M Broeders, Jennifer D Brooks, Tim Carver, Sue-Ling Chang, Jocelyne Chiquette, Éric Demers, Douglas F Easton, Andrea Eisen, Laurence Eloy, D Gareth R Evans, Samantha Fienberg, Yann Joly, Raymond H Kim, Bartha M Knoppers, Corinne Labeau-Caouette, Johanne Lessard, Aisha Lofters, Hermann Nabi, Jean-Sébastien Paquette, Nora Pashayan, Amanda J Sheppard, Tracy L Stockley, Meghan J Walker, Anna M Chiarelli, Jacques Simard, Michel Dorval","doi":"10.1016/j.gim.2025.101453","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101453","url":null,"abstract":"<p><strong>Purpose: </strong>To examine the psychological and emotional outcomes of personalized breast cancer risk communication up to one year post-disclosure in a risk-stratified breast screening pre-implementation study (PERSPECTIVE I&I).</p><p><strong>Methods: </strong>Among 3753 females aged 40-69, unaffected by breast cancer, with a prior mammogram, who underwent multifactorial risk assessment to estimate their 10-year breast cancer risk, 2734 completed follow-up questionnaires up to one year post-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.</p><p><strong>Results: </strong>Breast cancer worry and psychological distress scores remained low after risk communication and at one year follow-up. Up to one year post-disclosure, small significant differences in breast cancer worry were observed between risk levels. Decisional regret was very low one year after risk communication. Lower levels of decisional regret were significantly associated with some factors, including higher satisfaction with the information received.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"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":"Optical genome mapping improves clinical interpretation of constitutional copy number gains and reduces their VUS burden.","authors":"Avinash V Dharmadhikari, Alexander L Markowitz, Jennifer Han, Dolores B Estrine, Dong Xu, Katherine Ma, Cindy Fong, Bridget A Fernandez, Matthew A Deardorff, Ryan J Schmidt, Jianling Ji, Gordana Raca","doi":"10.1016/j.gim.2025.101452","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101452","url":null,"abstract":"<p><strong>Purpose: </strong>Genomic structure of copy number gains is critical for their clinical interpretation, but cannot be determined by chromosomal microarray (CMA) analysis, which does not provide information about chromosomal location and orientation of multiplied regions. We thus hypothesized that in CMA testing gains have higher probability than losses to be classified as VUS, and that structural information from Optical Genome Mapping (OGM) may improve their interpretation.</p><p><strong>Methods: </strong>Using a chi-square test we assessed the association between classification of copy number variants as VUS and their type (gains vs. losses) in a cohort of 4,073 CMA cases. Thirty-three VUS gains involving disease-associated genes were characterized by OGM to evaluate if OGM data enables their more conclusive clinical interpretation.</p><p><strong>Results: </strong>The proportion of variants reported as VUS compared to Likely-pathogenic/Pathogenic was significantly higher for gains than losses, confirming their increased VUS burden. OGM successfully determined genomic structure for all 33 copy number gains, showing that 26/33 were tandem duplications and 7/33 were complex rearrangements. Structural information facilitated clinical interpretation in majority of the cases; it supported benign nature for 27/33 gains and was inconclusive or supported pathogenic role for 6/33. An estimated 20% of reported VUS gains would not have been reportable if we had OGM data.</p><p><strong>Conclusion: </strong>We illustrate a specific advantage of OGM compared to CMA: in addition to detecting both copy number variants and balanced rearrangements, OGM improves clinical interpretation of copy number gains by providing structural information, and is thus expected to significantly decrease their VUS burden.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101452"},"PeriodicalIF":6.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002978","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, Raymond C Caylor, Olivia D'Annibale, Michelle McClure, TaraChandra Narumanchi, Laura M Sack, Sarah T South","doi":"10.1016/j.gim.2025.101391","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101391","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101391"},"PeriodicalIF":6.6,"publicationDate":"2025-05-02","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":"Smith-Lemli-Opitz Syndrome: Clinical, Biochemical, and Genetic Insights With Emerging Treatment Opportunities.","authors":"Amy Kritzer, Rana Dutta, Tiziano Pramparo, Jolan Terner-Rosenthal, Pamela Vig, Robert D Steiner","doi":"10.1016/j.gim.2025.101450","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101450","url":null,"abstract":"<p><p>Smith-Lemli-Opitz syndrome (SLOS), also known as RSH syndrome, is an inborn error of cholesterol biosynthesis first described in 1964. Since then, significant advances have been made in understanding its pathophysiology, both during fetal development and postnatally. Cholesterol is a crucial lipid in the body, especially in the central nervous system, which accounts for nearly 25% of the body's total cholesterol. Cholesterol deficiency in SLOS can lead to congenital malformations and severe neurodevelopmental disabilities. The biochemical and genetic bases of SLOS have been elucidated. Reduced or absent 7-dehydrocholesterol reductase (DHCR7) enzymatic activity results not only in cholesterol deficiency but also in accumulation of 7-dehydrocholesterol, 8-dehydrocholesterol, and toxic oxysterol metabolites, which contribute to the pathophysiology of SLOS and correlate variably with the severity of its clinical symptoms. Despite decades of research, the clinical recognition of SLOS remains challenging due to the condition's multisystemic nature and noteworthy phenotypic variability. This review provides an up-to-date summary of major research advances in the study of SLOS with a focus on clinical manifestations and biochemical and genetic findings, which taken together facilitate recognition and diagnostic confirmation. Additionally, we recap past and current efforts in therapeutic development and offer guidance for disease management.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101450"},"PeriodicalIF":6.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984019","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":"Reconciling competencies in undergraduate medical genetics education: APHMG versus PCME competencies","authors":"Rachel D. Burnside ,&nbsp;Megan Boothe ,&nbsp;David H. Ledbetter ,&nbsp;Heather Stalker ,&nbsp;Petr Starostik ,&nbsp;Pamela Trapane","doi":"10.1016/j.gim.2025.101448","DOIUrl":"10.1016/j.gim.2025.101448","url":null,"abstract":"<div><h3>Purpose</h3><div>We wanted to understand whether there were gaps within and/or between the Association of Professors of Human and Medical Genetics (APHMG) and the Association of Pathology Chairs (APC) published competencies for undergraduate medical education pertaining to topics in medical and/or laboratory genetics.</div></div><div><h3>Methods</h3><div>This study compared and contrasted the APHMG and APC competencies related to genetics to identify gaps between and within each to inform the closure of those gaps in undergraduate medical education curriculum development for medical and laboratory genetics at the University of Florida.</div></div><div><h3>Results</h3><div>Gaps were identified within and between both documents, many relating to neoplasia for nonheritable cancers and various topics related to laboratory genetics, such as interpretation of results, principles of laboratory diagnostics, and explaining results to others.</div></div><div><h3>Conclusion</h3><div>APHMG and APC should consider the gaps identified in this study in future updates to their respective competencies. Additionally, medical school curriculum committees may also wish to consider addressing these gaps in the development of medical genetics curricula.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101448"},"PeriodicalIF":6.6,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993102","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, safety, and tolerability of chenodeoxycholic acid (CDCA) in adult patients with cerebrotendinous xanthomatosis (RESTORE): A randomized withdrawal, double-blind, placebo-controlled, crossover phase-3 study","authors":"Yaz Y. Kisanuki ,&nbsp;Paulo R. Nobrega ,&nbsp;Ryan Himes ,&nbsp;Suman Jayadev ,&nbsp;John A. Bernat ,&nbsp;Vikram Prakash ,&nbsp;James B. Gibson ,&nbsp;Austin Larson ,&nbsp;Paulo Sgobbi ,&nbsp;Andrea E. DeBarber ,&nbsp;Edward Murphy ,&nbsp;Brian Fedor ,&nbsp;Cheryl Wong Po Foo ,&nbsp;Rana Dutta ,&nbsp;Michael Imperiale ,&nbsp;Will Garner ,&nbsp;Joanne Quan ,&nbsp;Pamela Vig ,&nbsp;P. Barton Duell ,&nbsp;Sarah Perez ,&nbsp;Wladimir Bocca Vieira de Rezende Pinto","doi":"10.1016/j.gim.2025.101449","DOIUrl":"10.1016/j.gim.2025.101449","url":null,"abstract":"<div><h3>Purpose</h3><div>Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in <em>CYP27A1</em>, resulting in sterol 27-hydroxylase deficiency and accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, diarrhea, cataracts, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The effects of CDCA withdrawal on CTX biomarkers and safety in adult patients were evaluated.</div></div><div><h3>Methods</h3><div>Patients (≥16 years) received CDCA 750-mg/day for 2 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for 2 4-week periods. Key endpoints included changes from baseline in CTX biomarkers (23S-pentol, cholestanol, 7αC4, 7α12αC4) and the proportion of patients requiring CDCA rescue during DB periods.</div></div><div><h3>Results</h3><div>CDCA withdrawal resulted in a 20-fold increase in 23S-pentol and increases in cholestanol (2.8-fold), 7αC4 (50-fold), and 7α12αC4 (14-fold). During the DB withdrawal periods, 61% of participants on placebo required rescue medication. CDCA treatment was well tolerated; the most common treatment-emergent adverse events were diarrhea and headache, most of them mild/moderate in severity and not considered treatment related.</div></div><div><h3>Conclusion</h3><div>CDCA withdrawal caused statistically significant increases in CTX biomarkers and necessitated rescue therapy in most participants. CDCA treatment is critical for control of biochemical abnormalities and helps avoid disease progression.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101449"},"PeriodicalIF":6.6,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964110","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, Sarah Bick, Sophia Adelson, Nils Gehlenborg, Laura M Amendola, François Boemer, Alison J Coffey, Nicolas Encina, Alessandra Ferlini, Janbernd Kirschner, Bianca E Russell, Laurent Servais, Kristen L Sund, Ryan J Taft, Petros Tsipouras, Hana Zouk, Robert C Green, Nina B Gold, David Bick, Mattia Gentile, Paola Orsini, Romina Ficarella, Maria Luisa Valente, Emanuela Ponzi, Athina Ververi, Maria Koutsogianni, Huang Xinwen, Xiao Rui, Zhao Zhengyan, Matthew J Pelo, Jovanka King, Carol Siu, Karin Kassahn, Stefaan Sansen, Enrico Bertini, Aldona Zygmunt, Sophia Adelson, Mattia Gentile, Mette Nyegaard, Emanuele Agolini, Jessica Giordano, Justin O'Sullivan, Aljazi Al-Maraghi, Ulrich Glumer Jensen, Jelili Ojodu, Karla Alex, David Godler, Paola Orsini, Fowzan Alkuraya, Nina Gold, Andrea Oza, Ammira Alshabeeb Akil, Aaron Goldenberg, Katrina Paleologos, Munira Alshehri, Katie GoldenGrant, Richard Parad, Derek Ansel, Cassie Goldman, Holly Peay, Niki Armstrong, José Manuel González de Aledo-Castillo, Matthew Pelo, Matthew Aujla, Daniel Gottlieb, Carolyn Philstrom, Don Bailey, Robert Green, Dominique Pichard, Mei Baker, Christopher Greene, Amanda Pichini, Jorune Balciuniene, Brooke Greenstein, Holly Pickering, Andrew Barry, Scott Grosse, Michelle Pirreca, Bruce Bennetts, Annette Grueters, Malgorzata Ponikowska, Melissa Berenger, Gulcin Gumus, Amy Ponte, Jonathan Berg, Kelly Hagman, Andreas Posch, Donna Bernstein, Kevin Hall, Cynthia Powell, Arindam Bhatatcharjee, Aymeric Harmant, Liana Protopsaltis, Sucheta Bhatt, Sally Hartmanis, Yeyson Quevedo, David Bick, Robin Hayeems, Marianna Raia, Tracey Bishop, Rose Heald, Rebecca Reimers, Asaf Bitton, Madhuri Hegde, Andy Rohrwasser, François Boemer, Rebecca Heiner-Fokkema, Paul Rollier, Natasha Bonhomme, Lidewij Henneman, Lene Rottensten, George Bowley, Becca Hernan, Irakli Rtskhiladze, Brenna Boyd, Charlotte Hobbs, Nabihah Sachedina, Heiko Brennenstuhl, Ingrid Holm, George Sahyoun, Steven Brenner, Layla Horwitz, Aditi Satija, Mairead Bresnahan, Zhanzhi Hu, Christian Schaaf, Thomas Brewster, Maria Iascone, Jennifer Schleit, P J Brooks, Ken Irvine, Richard Scott, Katya Broomberg, Guanjun Jin, Lauren Scully, Amy Brower, Kelsey Kalbfleisch, Stacey Seeloff, Gemma Brown, Ines Kander, Laurent Servais, James Buchanan, Lucy Kaplun, Nidhi Shah, Caleb Bupp, Dalia Kasperaviciute, Maija Siitonen, Candance Cameron, Karin Kassahn, Sikha Singh, Lauren Capacchione, Leni Kauko, Carol Siu, Diana Carli, Riina Kaukonen, Hadley Smith, Onassis Castillo Ceballo, Nicole Kelly, Lisa Sniderman King, Kee Chan, Dhayo Khangsar, Neal Sondheimer, Jillian Chance, Jovanka King, Lourdes St George, Georgia Charalambidou, Clare Kingsley, Zornitza Stark, Winnie Chen, Stephen Kingsmore, Robert Steiner, Yun-Ru Chen, Brian Kirmse, Ulrik Stoltze, Wendy Chung, Rachel Klein, Asbjørg Stray-Pedersen, Brian Chung, Stefan Koelker, Kristen Sund, Megan Clarke, Youssef Kousa, Paris Tafas, Susan Clasper, Elizaveta Krupoderova, Polakit Teekakirikul, F Sessions Cole, Paul Kruszka, Dimitrios Thanos, Heidi Cope, Katherine Langley, Audrey Thurm, Stephanie Coury, Ciara Leckie, Meekai To, Tony Cox, Emmanuelle Lecommandeur, Petros Tsipouras, Tamara Dangouloff, David Ledbetter, Alice Tuff-Lacey, Earnest James Paul Daniel, Pamela Lee, Heather Turner, Katrin Eivindardottir Danielsen, Beomhee Lee, Philip Twiss, Emeline Davoine, Camille Level, Fiona Ulph, Tom Defay, Celine Lewis, Daniel Uribe, Geethanjali Devadoss Gandhi, Anna Lewis, Tiina Urv, Joseph Dewulf, Ruby Liu, Cora Vacher, Lisa Diller, Mauro Longoni, Kris Van Den Bogaert, Pakhi Dixit, Alberte Lundquist, Mirjam van der Burg, Martijn Dolle, Sebastian Lunke, Eva Van Steijvoort, Lilian Downie, Kate MacDuffie, Yiota Veloudi, Erin Drake, Ankit Malhotra, Elizabeth Vengoechea, Suzanne Drury, Lionel Marcelis, Els Voorhoeve, Annelotte Duintjer, Maria Martinez-Fresno, Martin Vu, Bugrahan Duz, Gert Matthijs, Melissa Wasserstein, David Eckstein, Roberts Melbardis, Michael Watson, Matthew Ellinwood, Jessica Merritt, Bryn Webb, Katarzyna Ellsworth, Radja Messai Badji, Anna Wedell, Sarah Elsea, Lou Metherell, Thomas Westover, Nicolas Encina, Nanna Balle Mikkelsen, Alexandra Wiedemann, Harriet Etheredge, Laura Milko, Meredith Wright, Laurence Faivre, Nicole Miller, Cindy Wu, Alessandra Ferlini, Thomas Minten, Julie Yeo, Monica Ferrie, Sian Morgan, Nancy Yin-Hsiu Chien, Terri Finkel, Katarzyna Mosiewicz, Shamila Yusuff, Petra Furu, Ulrike Mütze, Tomasz Zemojtel, Jamie Galarza-Cornejo, Sukhvinder Nicklen, Bethany Zettler, Ya Gao, Minna Niemela, Zhengyan Zhao, Judit Garcia-Villoria, Dau-Ming Niu, Joanna Ziff, Liz Gardner, Sarah Norris, Rebekah Zimmerman, Amy Gaviglio, Antonio Novelli, Michela Zuccolo, Michael Gelb, Arwa Nusair","doi":"10.1016/j.gim.2025.101443","DOIUrl":"10.1016/j.gim.2025.101443","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>We assembled a dataset comprising 25 characteristics about each of the 4,390 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.</p><p><strong>Results: </strong>Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4,299, 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 (AUC = 0.915, R² = 84%).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101443"},"PeriodicalIF":6.6,"publicationDate":"2025-04-25","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}

{"title":"Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status","authors":"Chris Odhams ,&nbsp;Hywel J. Williams","doi":"10.1016/j.gim.2025.101447","DOIUrl":"10.1016/j.gim.2025.101447","url":null,"abstract":"<div><h3>Purpose</h3><div>Identifying the pathogenic variant in a patient with rare disease (RD) is the first step in ending their diagnostic odyssey. De novo (Dn) variants affecting protein-coding DNA are a well-established cause of Mendelian disorders in patients with RD. Constrained coding regions (CCRs) are specific segments of coding DNA that are devoid of functional variants in healthy individuals.</div></div><div><h3>Methods</h3><div>We evaluated the diagnostic utility of incorporating combined Dn/CCR status into the variant prioritization cascade for patients with RD that have undergone genomic sequencing. Using the Genomics England 100,000 Genomes Project v12, we selected 3090 trios that have undergone diagnostic evaluation and been analyzed with an advanced Dn identification pipeline.</div></div><div><h3>Results</h3><div>Our analysis shows that the diagnostic rate increased from 71% in the full cohort to 87% for Dn/CCR variants. Of note, manual evaluation of the Dn/CCR variants from undiagnosed patients with clinical follow-up revealed a diagnosis for 13 further patients. This outcome increases the diagnostic rate for Dn/CCR variants to 91% and suggests that the application of this metric can prioritize diagnostic variants in undiagnosed patients.</div></div><div><h3>Conclusion</h3><div>We demonstrate the potential clinical utility of performing bespoke Dn analyses of patients with RD and for incorporating CCR information into the filtering cascade to prioritize pathogenic variants.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101447"},"PeriodicalIF":6.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998043","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":"Evaluating the return of additional findings from the 100,000 Genomes Project: A mixed methods study exploring participant experiences of receiving secondary findings from genomic sequencing.","authors":"Bethany Stafford-Smith, Morgan Daniel, Michelle Peter, Jana Gurasashvili, Rashida Baptiste, Xavier Bracke-Manzanares, Lamprini Georgiou, Adele Green-Armytage, Blanche Griffin, Bethany Lumborg, Ben Paternoster, Emma Smith, Meena Balasubramanian, Lucy Bownass, Paul Brennan, Ruth Cleaver, Virginia Clowes, Philandra Costello, Bianca DeSouza, Louise Dubois, Angela George, Elaine George, Rachel Harrison, Lara Hawkes, Steve E Humphries, Alan Jones, Elizabeth A Jones, Alison Kraus, Deborah Holiday, Meriel McEntagart, Suresh Somarathi, Amy Taylor, Vishakha Tripathi, Stephen Morris, Lyn S Chitty, Melissa Hill","doi":"10.1016/j.gim.2025.101446","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101446","url":null,"abstract":"<p><strong>Purpose: </strong>100,000 Genomes Project participants could consent to receive additional findings (AFs) for variants associated with susceptibility to cancer and familial hypercholesterolemia (FH). Here we evaluate stakeholder experiences to inform clinical practice.</p><p><strong>Methods: </strong>Mixed-methods study conducted at 18 sites across England that comprised a cross-sectional survey and interviews with participants who received a positive AF (PAF), and interviews with participants who had no AFs (NAF).</p><p><strong>Results: </strong>There were 146 surveys followed by 35 interviews with PAF participants, and 29 interviews with NAF participants. Surveys found that PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members. Experiences differed by PAF type; cancer PAF participants were often initially shocked and anxious, and found telling family members challenging compared to participants with an FH PAF. Whilst most experiences of NAF results were positive, some misunderstandings were identified. Participants supported returning AFs when offering genome sequencing.</p><p><strong>Conclusion: </strong>Patient experiences of receiving AFs were primarily positive and there is support for offering AFs routinely. Considerations for offering AFs in clinical practice include adapting approaches tailored to individual conditions and greater support for people with a NAF result.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101446"},"PeriodicalIF":6.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013679","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 CAP/ACMG CYCGH proficiency testing program: 10 years in review","authors":"Yassmine Akkari ,&nbsp;Laura Conlin ,&nbsp;Diana DeAvila ,&nbsp;Juli-Anne Gardner ,&nbsp;Jaimie Halley ,&nbsp;Gordana Raca ,&nbsp;Reha M. Toydemir ,&nbsp;Karen Tsuchiya ,&nbsp;Catherine Rehder ,&nbsp;CAP/ACMG Cytogenetics Committee","doi":"10.1016/j.gim.2025.101445","DOIUrl":"10.1016/j.gim.2025.101445","url":null,"abstract":"<div><h3>Purpose</h3><div>The College of American Pathologists has offered proficiency testing (PT) for the detection of copy-number variations (CNV) in the constitutional setting (CYCGH) since 2008. We review and summarize data from the CYCGH PT program, including participant performance over time, changes made to the program, and ungraded challenges.</div></div><div><h3>Methods</h3><div>The PT challenges from 2011 through 2021 (22 total mailings) and changes to the program over time were reviewed. Laboratory enrollment and performance were assessed.</div></div><div><h3>Results</h3><div>Overall participation has increased over time, and laboratories have maintained a high level of proficiency. The major changes to the program have occurred twice during the time span examined. Reasons for challenges not meeting consensus were varied. The use of ungraded challenges was also discussed.</div></div><div><h3>Conclusion</h3><div>The CYCGH PT program is challenging because it assesses both analytical performance and interpretation as a single analyte. The program has evolved over time to address the changes in the field of CNV detection. During this time, additional technologies with the ability to detect CNVs have emerged, and the possibility of developing a platform-agnostic CNV PT program is being explored.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101445"},"PeriodicalIF":6.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991631","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}