Genetics in Medicine最新文献

{"title":"Mainstreaming genetic testing: Evaluation of the Australian Familial Melanoma Clinic.","authors":"Jennifer Berkman, Clare Primiero, Centaine Snoswell, Courtney K Wallingford, Betsy Peach, Emily DeBortoli, Xiaohua Shen, Helmut Schaider, Kiarash Khosrotehrani, Tatiane Yanes, H Peter Soyer, Aideen McInerney-Leo","doi":"10.1016/j.gim.2026.102742","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102742","url":null,"abstract":"<p><strong>Purpose: </strong>Familial melanoma genetic testing (GT) guides management but is rarely offered due to limited clinical genetics capacity. We used the RE-AIM framework to evaluate a new Australian Familial Melanoma Clinic (FMC), which integrated comprehensive dermatology examination and GT.</p><p><strong>Methods: </strong>To inform the RE-AIM domains, demographic and clinical data were collected prospectively. A cost-minimization approach compared costs per patient associated with an embedded genetic counselor in a specialist department compared with referral to specialist genetics services. Experiential training of dermatology clinicians was evaluated qualitatively to capture impact. Data were mapped to the RE-AIM domains.</p><p><strong>Results: </strong>284 patients (September 2021-August 2024) were referred predominantly by general practitioners (43%) and dermatologists (26%). 256/284 (90%) were eligible, 246/256 (96%) accepted testing, and 37/246 (15%) tested positive (probands and relatives). Average staffing costs/patient were $83 (FMC) and $125 (genetics service). Total costs/patient, excluding infrastructure costs, were $560 and $620 for the FMC and genetics service, respectively. FMC benefits included improved GT access and fewer appointments. Clinicians reported high satisfaction and increased genomic confidence.</p><p><strong>Conclusion: </strong>The embedded genetic counselor model improved access to melanoma GT alongside streamlined dermatological assessment for high-risk individuals. Testing uptake was high, the model-of-care is cost-effective, and clinicians reported positive experiences.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102742"},"PeriodicalIF":6.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108676","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 Pilot Study of the Hereditary Heart Disease Risk Algorithm and User Experience of the Family Health Risk Calculator.","authors":"Regan Webber, Hibatallah Khafagy, Natali Zecchino, Alberta Nomo, Yue Yu, Patricia Parker, Shelly Hovick, Kevin Sweet, Elizabeth Jordan","doi":"10.1016/j.gim.2026.102738","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102738","url":null,"abstract":"<p><strong>Purpose: </strong>Family Health Risk Calculator (FHRC) is a self-administered web tool that collects personal and family history (FH) and identifies individuals qualifying for genetic testing for hereditary heart disease (HHD) and cancer risk. This pilot study evaluated the updated HHD algorithm and user experience in a high-risk adult population.</p><p><strong>Methods: </strong>A retrospective chart review assessed concordance between FHRC HHD assessment and genetic testing recommendations by cardiovascular genetic counselors (CVGC) at an academic medical center. User experience was evaluated using the Post-Study System Usability Questionnaire (PSSUQ) and semi-structured interviews.</p><p><strong>Results: </strong>FHRC and CVGC assessment for HHD were concordant in 94% (n=232) of elevated (n=230) and average risk (n=2) cases. Fifteen percent (n=34) of elevated risk individuals met criteria in personal history only, 36% (n=83) in FH only, and 49% (n=113) in both. Fourteen assessments were discordant: 8 involved FH of specific genetic diagnoses and others included diagnoses not integrated in FHRC. Interviewed individuals (n=19) found FHRC user-friendly and scored it highly on the PSSUQ (mean 2.04/7). Limited FH knowledge was identified as a barrier.</p><p><strong>Conclusion: </strong>The FHRC HHD algorithm showed high concordance with clinical assessment and favorable usability in a high-risk adult population, though refinements are needed before broader population implementation.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102738"},"PeriodicalIF":6.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080706","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":"More Than Screening: What Does Equity in Reproductive Genetics Look Like?","authors":"Asha N Talati, Andrea Johnson, Neeta L Vora","doi":"10.1016/j.gim.2026.102730","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102730","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102730"},"PeriodicalIF":6.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074451","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":"Succinate dehydrogenase (SDHB, SDHC, SDHD) gene variants significantly modify clinical outcomes in paraganglioma-pheochromocytoma but have a limited impact on head and neck paraganglioma.","authors":"Jean-Pierre Bayley, Lauren Fishbein, Scott Akker, Johannes A Rijken, Mercedes Robledo, Alberto Cascon, Mariola Pęczkowska, Andrzej Januszewicz, Elena Rapizzi, Letizia Canu, Samantha E Greenberg, Luke Buchmann, Anne Naumer, Tobias Else, María-Dolores Chiara, Oksana Hamidi, Alexandre Persu, Miikka Vikkula, Bernadette P M van Nesselrooij, Nicolasine D Niemeijer, Agnieszka Kotecka-Blicharz, Malgorzata Oczko-Wojciechowska, Pamela L Brock, Lawrence S Kirschner, Sara Donato, Branca Maria Cavaco, Roderick Clifton-Bligh, Indrani Sen, Alfonso Massimiliano Ferrara, Yasir S Elhassan, John Ayuk, D Aled Rees, Isabelle Bourdeau, Stefanie Parisien-La Salle, Patricia L M Dahia, Yumie Rhee, Anna L Mitchell, Paul Brennan, Uberta Verga, Giulia Carosi, Giovanna Mantovani, Moon-Woo Seong, Jee-Soo Lee, Jung Hee Kim, Susan Richter, Christina Pamporaki, Matthias Kroiss, Hanna Remde, Martin Fassnacht, Felicia Alexandra Hanzu, Ruth T Casey, Laurent Brunaud, Claire Nomine-Criqui, Delphine Clabaut, Guillaume Gauchotte, Tobias Akerstrom, Joakim Crona, Xiaohong Chen, Elena Navarro, Dueñas Disotuar, Maria Del Castillo Tous, Hans K Ghayee, Juan Pablo Perdomo Rodriguez, Lisa A Brown, Jose Luis Llorente, Miguel Arístegui, Rosalia Souviron, Thomas C Bower, William F Young, Francesca Schiavi, Stefania Zovato, Eugenie Lim, Aklima Khatun, Charlotte L Hall, Diana Benn, Catherine Luxford, Tristan Richardson, Timo Deutschbein, Ana Romero Lluch, Seung Hun Lee, Cristina Alvarez Escola, Marta Araujo-Castro, Ma'en Al-Mrayat, Karen R Mullan, Milad Darrat, Khin Swe Myint, Rupa Ahluwalia, Georgia Sinclair, Tricia Tan, Lisa Yang, Bijay Vaidya, Sarah Benyon, Alicja Szatko, Piotr Glinicki, Ronald R de Krijger, C René Leemans, Bart-Jeroen Petri, Henri J L M Timmers, Peter H Bisschop, Richard R Feelders, Koen M A Dreijerink, Michiel N Kerstens, Wouter T Zandee, Erik F Hensen, Hartmut P H Neumann, Eamonn R Maher, Eleonora P M Corssmit, Jeroen C Jansen, Peter Devilee","doi":"10.1016/j.gim.2026.102725","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102725","url":null,"abstract":"<p><strong>Purpose: </strong>Succinate dehydrogenase (SDH) gene variant types differentially influence risk for thoracic-abdominal paraganglioma-pheochromocytoma (PPGL) and head and neck paraganglioma (HNPGL), but quantitative correlations are lacking.</p><p><strong>Methods: </strong>In this genotype-phenotype study of 2706 patients with PPGL-HNPGL and SDH variants from 57 centres worldwide, we analysed correlations of SDHB, SDHC and SDHD variants with tumour incidence, age of diagnosis, risk of metastasis and other clinical characteristics.</p><p><strong>Results: </strong>SDH variant types (missense variants vs. protein truncating variants (PTVs)) had a major differential impact on PPGLs, but little effect on HNPGLs. Combined PPGL and HNPGL (sPP&pHNPGL) was significantly more common in patients with SDHD variants, especially PTVs. Compared to PTVs, SDH missense variants showed broader clinical variability. Common vs. rare variants appeared to differentially impact clinical outcomes, including metastasis. Furthermore, specific SDH variants exhibited distinct clinical profiles. Regarding novel general findings, patients with SDHB (but not SDHC or SDHD) variants were diagnosed with PPGLs significantly earlier than HNPGLs, and paediatric cases with HNPGL showed elevated risk for metastasis and sPP&pHNPGL. We also observed an elevated risk for sPP&pHNPGL in males.</p><p><strong>Conclusion: </strong>SDH variant types exhibit tissue-specific clinical differences, significantly influencing PPGL but not HNPGL clinical outcomes and underlining biological differences between precursor tissues.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102725"},"PeriodicalIF":6.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080637","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":"Not the end of the road: Achieving diagnoses following non-diagnostic exome sequencing: experiences at a clinical site of the Undiagnosed Diseases Network.","authors":"Rebecca C Spillmann, Nicole Walley, Kelly Schoch, Mohamad A Mikati, Vaidehi Jobanputra, Patrick Shea, Vandana Shashi","doi":"10.1016/j.gim.2026.102736","DOIUrl":"10.1016/j.gim.2026.102736","url":null,"abstract":"<p><strong>Purpose: </strong>Most participants who undergo exome sequencing (ES) remain undiagnosed. Since clinical ES reanalysis and clinical genome sequencing (GS) provide incremental diagnoses in only 5-15%, better resolution approaches to non-diagnostic ES are needed.</p><p><strong>Methods: </strong>Retrospective review of non-diagnostic NGS (ES/GS), at one site of the Undiagnosed Diseases Network (UDN), to assess the diagnostic approaches of ES/GS research reanalysis, clinical GS, non-ES/GS genetic testing and achieving diagnoses from clinical information.</p><p><strong>Results: </strong>77/192 (40%) participants with prior non-diagnostic NGS (ES/GS) obtained 80 diagnoses, including known disorders (n=50) and novel gene-disease associations (n=30). Research reanalysis of raw data from prior ES and UDN GS yielded the highest diagnoses (54%), followed by clinical ES/GS (27%), genetic testing other than ES/GS (11%) and clinical diagnoses (8%). Most causal variants were single nucleotide variants (SNVs- 78%) and most were coding (88%). Most (72%) genetic diagnoses should have occurred with prior ES; frequent reasons for diagnoses being overlooked were the prior laboratory not prioritizing: (a) novel gene variants (53%) and, (b) variants in known disorder genes due to perceived phenotypic mismatch (17%).</p><p><strong>Conclusions: </strong>An individualized approach to non-diagnostic NGS increased the diagnosis rate beyond reflexive GS. Most subsequent diagnoses and novel gene discoveries were from prioritization of variants amenable to ES.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102736"},"PeriodicalIF":6.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069454","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 Economic Costs of Genetic Counseling: A Combined Expert Perspective and Systematic Review.","authors":"Varinder Jeet, Julie Cigrang, Amanda Willis, Henry Cutler, Mary-Anne Young","doi":"10.1016/j.gim.2026.102739","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102739","url":null,"abstract":"<p><strong>Purpose: </strong>Genetic counseling (GC) is integral to personalized medicine, yet detailed estimates of its cost remain limited despite growing demand. This study systematically reviewed and synthesized evidence on GC costs, examined variations across settings, methodologies, and reported cost components.</p><p><strong>Methods: </strong>A systematic literature review was conducted following PRISMA guidelines across Embase and Ovid Medline databases. Studies were included if they reported GC costs. Data were extracted on study characteristics, methodologies, and reported costs. Costs were adjusted to 2024 values using OECD Consumer Price Index and converted to USD for comparability. A narrative synthesis approach was adopted due to methodological heterogeneity.</p><p><strong>Results: </strong>Nineteen of 1,487 screened studies met the inclusion criteria. Most relied on wage-based and time-based costing approaches, with limited use of systematic microcosting. Inflation-adjusted GC costs ranged widely ($72 to $1,970). Studies capturing only direct patient contact consistently reported lower costs than those incorporating indirect activities.</p><p><strong>Conclusion: </strong>Published GC costs vary markedly due to differences in costing scope, methodology, and healthcare systems. Standardized costing frameworks are needed to improve comparability across studies and support accurate planning, resource allocation, service design, and evaluation in genomic medicine.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102739"},"PeriodicalIF":6.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069490","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":"Universal versus guideline-based germline multigene panel testing in solid tumors: Diagnostic yield, variant of uncertain significance burden, and clinical actionability - A systematic review with meta-analysis.","authors":"Imad Barjij, Sarah Naciri, Sihame Lkhoyaali, Saoussane Kharmoum, Hanane Inrhaouen, Ibrahim Elghissassi, Saber Boutayeb, Hind Mrabti, Hassan Errihani","doi":"10.1016/j.gim.2026.102733","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102733","url":null,"abstract":"<p><strong>Purpose: </strong>To compare diagnostic yield, variant of uncertain significance (VUS) burden, and clinical actionability of universal versus guideline-based germline multigene panel testing in adults with solid tumors.</p><p><strong>Methods: </strong>PubMed, Embase, Web of Science, and Scopus were searched from inception to January 30, 2026. Studies reporting germline multigene testing outcomes in adult solid tumor populations were included. Risk of bias was assessed with validated tools. Proportions were pooled using random-effects models.</p><p><strong>Results: </strong>Among 144 included studies, 14 formed the comparative evidence set. In unselected cohorts, pooled diagnostic yield was 0.13 (95% confidence interval [CI], 0.11-0.17; I² = 98%), and pooled VUS burden was 0.40 (95% CI: 0.33-0.48; I² = 97%). In a two-study synthesis, National Comprehensive Cancer Network (NCCN) criteria sensitivity was 0.72 (95% CI: 0.67-0.76), indicating that approximately 28% of individuals with pathogenic or likely pathogenic variants would not meet the tested criteria.</p><p><strong>Conclusion: </strong>Universal germline multigene testing detects additional hereditary cancer predisposition beyond phenotype-based criteria but increases uncertain findings. Standardized actionability definitions and prospective comparative studies are needed to guide implementation.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102733"},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038132","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":"Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum.","authors":"Raman Kumar, Alison Gardner, Rudrarup Bhattacharjee, Shreya Agarwala, Clare L van Eyk, Mark A Corbett, Renee Carroll, Thessa Kroes, Tarin Ritchie, Rebekah de Nys, Danielle Mazurkiewicz, Wu Bing, Elizabeth E Palmer, Michael Field, Jolijn J A Verseput, Bert B A de Vries, Alexander J M Dingemans, Qi Zhang, Fuyi Li, Francois Bernier, Julie Lauzon, Robert Śmigiel, Juan Darío Ortigoza-Escobar, Angeles García-Cazorla, Alejandra Darling, Cornelius F Boerkoel, Stephanie Huynh, Gregory Costain, Tjakko J van Ham, Esmee Kasteleijn, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Ype Elgersma, Yvette van Ierland, Danielle Veenma, Dimitar Azmanov, Allison Goetsch Weisman, Carlos E Prada, Sandhya Parkash, Andrea L Rideout, W S Kerstjens-Frederikse, Jaime Vengoechea, Jan-Christoph Schoene-Bake, Francoise Devillard, Jasper van der Smagt, Noor A A Giesbertz, Andrew E Fry, Jana Jezkova, Antje Kampmeier, Alma Kuechler, Ute Grasshoff, Miriam Bertrand, Scott E Hickey, Jesse M Hunter, Mackenzie V Marr, Juliette Dupont, Stefania Bigoni, Alessandra Ferlini, Rita Selvatici, Nicolas Chatron, Gaetan Lesca, Louis Januel, Massimiliano Rossi, Curtis Rogers, Jessica M Davis, Fiona McKenzie, Felix Marbach, Laura Gieldon, Wolfgang M Schmidt, Amina Paquay, Reginald E Bittner, Simone Mahal, Günther Bernert, Ingrid Sinnerbrink, Linda Goodwin, Sandra Cooper, Natalja Bannink, Lachlan A Jolly, Julie McGaughran, Alexis Bosman, Rebecca Hernan, Wendy K Chung, Irene Valenzuela, Ivon Cuscó, Agatha Schlüter, Aurora Pujol, Luis Alberto Pérez-Jurado, Jozef Gecz","doi":"10.1016/j.gim.2026.102734","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102734","url":null,"abstract":"<p><strong>Purpose: </strong>TRranscription EXport (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, mRNA export, genome stability, cell differentiation and survival. We aimed to determine if variation in the TREX subunits, in addition to THOC2 and THOC6 genes, caused Neurodevelopmental Disorders.</p><p><strong>Methods: </strong>Through international collaboration we aggregated and assessed 40 individuals with high impact variants across four TREX subunit coding genes: THOC2 and THOC6 (known disease genes), and THOC7 and ALYREF (THOC4) (candidate disease genes).</p><p><strong>Results: </strong>On the background of considerable heterogeneity of neurodevelopmental and clinical outcomes, we noted that all TREX subunit variants impact cognitive functioning and development, speech and the respiratory systems as well as result in recognisable facial dysmorphism. We identified and studied five recurrent THOC2 variants, which give overlapping yet variable clinical presentations, including severe perinatal lethal arthrogryposis multiplex congenita (AMC). Using cells from 13 affected individuals, we show that their TREX subunit variants are generally partial loss of function (LoF), which alter protein localisation, protein stability, protein-protein interactions or delete internal or C-terminal protein functional domains. Cells from affected individuals from across all four TREX subunits studied show consistent, yet variable accumulation of DNA damage.</p><p><strong>Conclusion: </strong>The molecular, cellular and in silico data with the clinical presentations define a TREX spectrum disorder due to functional variation across multiple TREX subunits.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102734"},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038068","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":"Rescue of Proteus syndrome lethality in mice with prenatal miransertib treatment.","authors":"Shaima Raji Abdul Rahiman Sirajuddeen, Marjorie J Lindhurst, Megan Detels, Nathaniel Laughner, Jennifer Johnston, Lauren R Brinster, Leslie G Biesecker","doi":"10.1016/j.gim.2026.102732","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102732","url":null,"abstract":"<p><strong>Purpose: </strong>Proteus syndrome is caused by constitutive AKT1 activation, resulting in severe overgrowth and tumor susceptibility. We developed a mouse model, featuring endogenously regulated, mosaic expression of the Akt1 c.49G>A, p.(Glu17Lys) (Akt1 E17K) variant. Prior results showed that ubiquitous Akt1^E17K expression causes embryonic lethality. We hypothesized that a therapeutic effect of a small molecule could rescue the embryonic lethality and serve as a screen for the therapeutic potential of an agent.</p><p><strong>Methods: </strong>We first tested whether miransertib, an allosteric pan-AKT inhibitor can cross the placental barrier. To assess embryonic survival to birth, dams from timed matings between ACTB-Cre and Akt1^WT/flx mice were dosed at specific gestational time points.</p><p><strong>Results: </strong>Mice treated at 60 or 90 mg/kg/day showed a significantly increased, p=0.0003, proportion of neonatal survival (15/63 compared to 6/152). A startling observation was that several mutant βA-Akt1^WT/flx mice were not only born alive but were apparently healthy until nearly 18 months of age without postnatal miransertib treatment and showed a high variant allele fraction in nearly all tissues.</p><p><strong>Conclusion: </strong>Dose-dependent rescue of βA-Akt1^WT/flx embryos using miransertib validates the drug's potential as a therapeutic candidate. The βA-Akt1^WT/flx mouse model can serve as a platform for rapid preclinical drug testing for Proteus syndrome.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102732"},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038106","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":"Assessing Melanoma and Pancreatic Cancer Risks in Diverse CDKN2A Heterozygote Populations.","authors":"Colin C Young, Magan Trottier, Carolyn Horton, Maggie Feng, Amal Yussuf, Jacqueline Mersch, Amber Gemmell, Andrew Giles, Linda M Polfus, Marcy E Richardson","doi":"10.1016/j.gim.2026.102731","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102731","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102731"},"PeriodicalIF":6.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016632","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}