Genetics in Medicine Open最新文献

{"title":"Study design with responsible return of results for a fully remote genome sequencing study in individuals with Prader-Willi syndrome","authors":"Caroline J. Vrana-Diaz ,&nbsp;Jessica Bohonowych ,&nbsp;Jaimie L. Richards ,&nbsp;Brandon M. Wilk ,&nbsp;Manavalan Gajapathy ,&nbsp;Yael Bar-Peled ,&nbsp;Anna C. Harris ,&nbsp;Jessica J. Denton ,&nbsp;Donna Brown ,&nbsp;Elizabeth A. Worthey ,&nbsp;Theresa V. Strong","doi":"10.1016/j.gimo.2025.103448","DOIUrl":"10.1016/j.gimo.2025.103448","url":null,"abstract":"<div><h3>Purpose</h3><div>Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder affecting multiple systems. We describe the design and feasibility of a fully remote, patient group-led, genome sequencing (GS) study that will evaluate the impact of genetic variants on the frequency and severity of PWS clinical symptoms, with responsible return of results.</div></div><div><h3>Methods</h3><div>A total of 50 participants, or their legally authorized representative, provided consent via videoconference discussion and selected which genetic results would be returned. Participants were sent dried blood spot cards for GS and a buccal swab kit for orthogonal pharmacogenomics analysis. A subset of legally authorized representative LARs participated in semistructured interviews about their GS experience.</div></div><div><h3>Results</h3><div>All 50 participants completed the study and elected to receive their primary findings, and 48 of 49 participants who consented to receive pharmacogenomic information returned the buccal swab kit. Forty-seven participants consented to receive secondary findings per current American College of Medical Genetics guidelines; 2 had actionable results, with online genetic counseling support provided. Three families received medically significant findings related to variants associated with blood clot formation, which is important because individuals with PWS are at an increased risk for thrombotic events. Interview participants expressed a high degree of interest in the findings and emphasized the ease of participating in the study but felt the process was lengthy.</div></div><div><h3>Conclusion</h3><div>A fully remote GS study is feasible to perform within a rare disease population, and responsibly returning genetic findings that are important to families is achievable.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103448"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How to turn “minority tax” into “minority capital”","authors":"Maria Laura Duque Lasio ,&nbsp;John Paul Sánchez ,&nbsp;Fabiola Quintero-Rivera","doi":"10.1016/j.gimo.2025.103461","DOIUrl":"10.1016/j.gimo.2025.103461","url":null,"abstract":"<div><div>Efforts to increase diversity, equity, and inclusion (DEI) in academia have created additional opportunities and burdens for individuals from underrepresented groups. The “minority tax” or “cultural taxation” is defined as additional or extra responsibilities distinctly placed on minoritized faculty in the name of DEI efforts. The “minority tax” is something all too familiar to individuals from marginalized groups; however, this concept has not been addressed broadly in the context of the medical and human genetics workforce. In the 2023 American College of Medical Genetics and Genomics annual conference, the authors were given the opportunity to organize a plenary session solely dedicated to DEI with a focus on how to address the “minority tax” and turn it into “minority capital.” Approximately 400 individuals participated in the live Q&amp;A and polling, and almost 700 participants evaluated the session afterward. Although the concept of the minority tax was entirely new to some, for many others, this topic resonated deeply as part of their lived experiences. Quotes by participants showed the session’s influence on self-reflection, self-advocacy, and peer advocacy. Additional individual and institutional structured efforts are needed to help minoritized individuals gain awareness and knowledge to transform minority taxation to capital.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103461"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence-assisted clinical exome sequencing: Insights and outcomes from 822 pediatric diagnoses","authors":"Yinghong Pan,&nbsp;Patrick Danley,&nbsp;Tamar Kramer,&nbsp;Mehrdad Noruzinia,&nbsp;Karen Buser,&nbsp;Alexander N. Yatsenko,&nbsp;Daniel Bellissimo,&nbsp;Fen Guo","doi":"10.1016/j.gimo.2026.104488","DOIUrl":"10.1016/j.gimo.2026.104488","url":null,"abstract":"<div><h3>Purpose</h3><div>This retrospective study examined the clinical and genetic characteristics of pediatric patients undergoing clinical exome sequencing (ES) and evaluated the performance of a commercially available artificial intelligence (AI) platform that was integrated into our analysis pipeline.</div></div><div><h3>Methods</h3><div>ES was performed in 822 consecutive patients at a single clinical laboratory. AI-based tools were used to jointly assess genetic information and the proband’s Human Phenotype Ontology terms to support variant prioritization during the initial case review.</div></div><div><h3>Results</h3><div>A definitive molecular diagnosis was established in 22% (181 of 822) of index cases, while 40% (325 of 822) had variants of uncertain significance. Among those with a definitive diagnosis, 93% (168 of 181) had a single finding and 7% (13 of 181) had multiple findings. Of the 152 reported pathogenic/likely pathogenic variants in the fully resolved cases, 98.7% were successfully flagged by AI, and 75.0% ranked among the top 10 “most likely” variants.</div></div><div><h3>Conclusion</h3><div>Clinical ES provides a substantial diagnostic yield in complex pediatric disorders. Integration of AI-powered platforms can accelerate phenotype-driven variant prioritization and facilitate rare disease diagnostics, but underscores the need for careful validation and optimization in clinical workflows.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104488"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome and transcriptome sequencing reveal pathogenic activation of a pseudoexon in PKD1 via a de novo–common variant complex allele","authors":"Sangwoo T. Han,&nbsp;Atteeq U. Rehman,&nbsp;Sowmya Thirumalai Srinivasa,&nbsp;Alicia Lam,&nbsp;Michael Ficurilli,&nbsp;Vanessa Felice,&nbsp;Priya Krithivasan,&nbsp;Shruti Phadke,&nbsp;Avinash Abhyankar,&nbsp;Katherine Bergstrom,&nbsp;Jennifer A. Bassetti,&nbsp;Vaidehi Jobanputra","doi":"10.1016/j.gimo.2026.104407","DOIUrl":"10.1016/j.gimo.2026.104407","url":null,"abstract":"<div><h3>Purpose</h3><div>Despite improvements in and access to clinical genetic testing, many patients with classic phenotypes remain without a molecular diagnosis. Such cases may reflect variants in noncoding regions or complex alleles made up of disparate sequence variants. In this article, we report a patient with autosomal dominant polycystic kidney disease caused by a deep intronic de novo single-nucleotide substitution forming a dinucleotide variant, with an adjacent common single-nucleotide variant (formerly single-nucleotide polymorphism) inherited from an unaffected parent. Although neither variant alone was predicted to be pathogenic, together as a dinucleotide variant, they created a novel splice donor site that activated a pseudoexon within intron 16 of the <em>PKD1</em> gene.</div></div><div><h3>Methods</h3><div>Genome sequencing was paired with transcriptome sequencing to evaluate the dinucleotide variant within intron 16 of <em>PKD1</em>.</div></div><div><h3>Results</h3><div>Evaluation of RNA from patient cells confirmed the inclusion of a 114-bp pseudoexon and an in-frame premature termination codon into the <em>PKD1</em> messenger RNA transcript. This case identified a rare scenario in which the combination of 2 independently predicted benign nucleotide substitutions immediately adjacent to one another generated a pathogenic allele.</div></div><div><h3>Conclusion</h3><div>This case highlights the diagnostic utility of genome sequencing coupled with RNA sequencing to clarify the effects of a deep intronic variant, confirming a molecular diagnosis for a patient with a clear clinical diagnosis who had undergone years of inconclusive testing. Furthermore, this case cautions that similar events may underlie unsolved cases across other genes and disorders.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104407"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148553688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CFTR rescue in W1282X cystic fibrosis patient-derived intestinal organoids (PDIOs) mediated by translational readthrough-inducing drugs (TRIDs)","authors":"Riccardo Perriera ,&nbsp;Anabela S. Ramalho ,&nbsp;Francois Vermeulen ,&nbsp;Emanuele Vitale ,&nbsp;Ivana Pibiri ,&nbsp;Andrea Pace ,&nbsp;Laura Lentini","doi":"10.1016/j.gimo.2025.103472","DOIUrl":"10.1016/j.gimo.2025.103472","url":null,"abstract":"<div><h3>Purpose</h3><div>Pathogenic variants in the cystic fibrosis transmembrane conductance regulator (<em>CFTR</em>) gene result in dysfunctions of the CFTR protein, leading to cystic fibrosis (CF). This genetic disorder is characterized by severe symptoms in the respiratory and digestive systems.</div><div>Currently, highly effective CFTR modulator treatments, such as the Elexacaftor-Tezacaftor-Ivacaftor combination, may represent the primary therapeutic option for approximately 82% of people with cystic fibrosis who have at least 1 F508del variant. However, the remaining 18% with rare <em>CFTR</em> variants, including nonsense variants, often lack access to these therapies. Nonsense variants lead to nonfunctional CFTR proteins and contribute to more severe CF symptoms. Research efforts focus on understanding the effects of these variants on disease severity and response to treatment.</div></div><div><h3>Methods</h3><div>This study utilizes patient-derived intestinal organoids to evaluate the recovery of CFTR function in cells with nonsense variants.</div></div><div><h3>Results</h3><div>Specifically, we tested 3 translational readthrough-inducing molecules: NV848, NV914, and NV930. Our studies highlighted the positive effect of NV848 on patient organoid swelling, improving CFTR channel function, whereas NV914 and NV930 did not induce organoid swelling, similar to PTC124 treatment.</div></div><div><h3>Conclusion</h3><div>In conclusion, this study highlights the potential of translational readthrough-inducing molecules to restore CFTR function in cells with nonsense variants. By leveraging patient-derived intestinal organoids, our findings showed that NV848, in combination with Elexacaftor-Tezacaftor-Ivacaftor and the nonsense-mediated mRNA decay inhibitor NMDI14, enhances CFTR activity. This contributes to the development of personalized therapies for individuals with rare <em>CFTR</em> variants, addressing a critical unmet need in cystic fibrosis treatment.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103472"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P038: Expanding the HGD variant spectrum and addressing missing heritability in a 96-patient cohort","authors":"Irene Castillo ,&nbsp;Francis Rossignol ,&nbsp;NISC Comparative Sequencing Program ,&nbsp;Barbara Pusey ,&nbsp;Joy Bryant ,&nbsp;Carla Ciccone ,&nbsp;David Adams ,&nbsp;William Gahl ,&nbsp;May Christine Malicdan ,&nbsp;Stacie Loftus ,&nbsp;Wendy Introne","doi":"10.1016/j.gimo.2026.103529","DOIUrl":"10.1016/j.gimo.2026.103529","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103529"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P034: A real-world evidence study into the usage of olipudase alfa for acid sphingomyelinase deficiency in the United States","authors":"Judy Hull ,&nbsp;Neeraj Rawat ,&nbsp;Laurence Pollissard ,&nbsp;Gavin Harper ,&nbsp;Joe Conyers ,&nbsp;Rabiyah Sahar","doi":"10.1016/j.gimo.2026.103525","DOIUrl":"10.1016/j.gimo.2026.103525","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103525"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O06: Multi-omic evaluation of glycosylation restoration therapy in SLC35A2-CDG","authors":"Andrew Edmondson ,&nbsp;Joy Han ,&nbsp;Kishore Garapati ,&nbsp;Earnest James Paul Daniel ,&nbsp;Bobby Ng ,&nbsp;Hudson Freeze ,&nbsp;Miao He ,&nbsp;Akhilesh Pandey","doi":"10.1016/j.gimo.2026.104291","DOIUrl":"10.1016/j.gimo.2026.104291","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104291"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O11: Prevalence and tumor characteristics of patients with TMEM127 pathogenic variants in a large, pan-cancer cohort","authors":"Eva Vailionis ,&nbsp;Elise Fiala ,&nbsp;Ciyu Yang ,&nbsp;David Lin ,&nbsp;Anita Bowman ,&nbsp;Diana Mandelker ,&nbsp;Yelena Kemel ,&nbsp;Mohammad Abbass ,&nbsp;Lauren Banaszak ,&nbsp;Jada Hamilton ,&nbsp;Chimene Kesserwan ,&nbsp;Alicia Latham ,&nbsp;Ying Liu ,&nbsp;Yonina Murciano-Goroff ,&nbsp;Kenneth Offit ,&nbsp;Mark Robson ,&nbsp;Robert Sidlow ,&nbsp;Zsofia Stadler ,&nbsp;Maria Carlo","doi":"10.1016/j.gimo.2026.104297","DOIUrl":"10.1016/j.gimo.2026.104297","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104297"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P020: Baseline characteristics and medical history of participants enrolled in the MPS VII Disease Monitoring Program (DMP)","authors":"Christina Grant ,&nbsp;Raymond Wang ,&nbsp;Antonio Gonzalez-Meneses ,&nbsp;Roberto Giugliani ,&nbsp;Barbara Burton ,&nbsp;Maurizio Scarpa ,&nbsp;Terry Kho ,&nbsp;Ans van der Ploeg ,&nbsp;Esmeralda Martins ,&nbsp;Consuelo Durand ,&nbsp;Brigitte Chabrol ,&nbsp;Sean Daugherty ,&nbsp;Joel Hetzer ,&nbsp;Jeanne Cohen ,&nbsp;J. Lawrence Merritt","doi":"10.1016/j.gimo.2026.103511","DOIUrl":"10.1016/j.gimo.2026.103511","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103511"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147395218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}