Genetics in Medicine Open最新文献

{"title":"P001: Lower extremity alignment improvements correlate with physical functioning in children with achondroplasia treated with navepegritide: 52-week ApproaCH trial results*","authors":"Janet Legare , Leanne Ward , Daniel Hoernschemeyer , Hanne Hove , Carlos Bacino , Philippe Campeau , Paul Hofman , Josep Maria de Bergua Domingo , M. Jennifer Abuzzahab , Kevin Smit , Sasha Carsen , Andrew Tice , Stefan Jackowski , Maya Scharke , Meng Mao , Lærke Clement Freiberg , Michael Makara , Michael Ominsky , Aimee Shu , Ravi Savarirayan , Ciara McDonnell","doi":"10.1016/j.gimo.2026.103492","DOIUrl":"10.1016/j.gimo.2026.103492","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103492"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147396415","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":"P060: Low-cost self-pay testing and patient motivation facilitate genetic testing of unaffected individuals at risk for hereditary breast and ovarian cancer*","authors":"Juli Bollinger , Cabell Jonas","doi":"10.1016/j.gimo.2026.103551","DOIUrl":"10.1016/j.gimo.2026.103551","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103551"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147396597","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":"P059: Comprehensive somatic mutational profiling of triple-negative breast cancer reveals clinically actionable genetic alterations*","authors":"Pranay Tanwar , Harsh Goel , Atul Batra , Ajay Gogia","doi":"10.1016/j.gimo.2026.103550","DOIUrl":"10.1016/j.gimo.2026.103550","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103550"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147396598","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":"P018: Analysis of mitochondrial-targeted antioxidants shows improvement of bioenergetics in glutaric acidemia type 1 patient fibroblasts","authors":"Kara Sampson , Bianca Seminotti , Al-Walid Mohsen , Peter Wipf , Jerry Vockley","doi":"10.1016/j.gimo.2026.103509","DOIUrl":"10.1016/j.gimo.2026.103509","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103509"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147396729","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":"P017: Epigenome-wide DNA methylation profiling identifies distinct regulatory signatures of type 2 diabetes in the Bangladeshi population","authors":"Nilima Barman , M. Atiqul Haque , Abul B.M.M.K. Islam","doi":"10.1016/j.gimo.2026.103508","DOIUrl":"10.1016/j.gimo.2026.103508","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103508"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147396730","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":"RNA-guided clarity: The potential for resolving variant uncertainty in clinical exome sequencing","authors":"Grace E. VanNoy,&nbsp;Catherine Schultz,&nbsp;Brooklynn Gasser,&nbsp;Jessica Gage,&nbsp;Jessica Grzybowski,&nbsp;Carolyn Horton,&nbsp;Melissa Holman,&nbsp;Shoji Ichikawa,&nbsp;Emily Kudalkar,&nbsp;Melissa Samons,&nbsp;Heather Zimmermann,&nbsp;Marcy E. Richardson","doi":"10.1016/j.gimo.2026.104369","DOIUrl":"10.1016/j.gimo.2026.104369","url":null,"abstract":"<div><h3>Purpose</h3><div>Although RNA analysis holds potential to increase the diagnostic yield of exome sequencing (ES) for rare disease, its practical utility and barriers to its large-scale implementation have not been well studied. To quantify the impact of RNA analysis in clinical ES, we retrospectively assessed variants reported over a nearly 5-year period at a single clinical laboratory.</div></div><div><h3>Methods</h3><div>Reported variants and corresponding genes were assessed based on 4 eligibility criteria for RNA analysis at our laboratory: (1) suspected spliceogenic impact, (2) sufficient gene expression in blood, (3) characterized gene with at least moderate gene-disease validity, and (4) mechanism of disease is loss of function (LOF).</div></div><div><h3>Results</h3><div>A total of 1987 unique variants were reported on ES during the study period. In total, 11.4% (226/1987) were putative splicing variants, 68.2% (1355/1987) had sufficient gene expression in blood, 83.0% (1650/1987) were in a gene with a LOF mechanism, and 98.9% (1965/1987) occurred in characterized genes. When assessed on the 4 criteria combined, 7.6% (152/1987) of variants were eligible for RNA analysis. Of those variants, which were identified in 153 individuals, 35.5% (54/152) were variant of uncertain significance (VUS), representing 5.2% (54/1035) of all VUS reported. Nine cases were successfully recruited for retrospective RNA analyses, 7 of whom had VUS and 2 who had a likely pathogenic variant. Of the VUS, 71.4% (5/7) were upgraded, whereas 28.6% (2/7) remained a VUS. The 2 likely pathogenic variants remained likely pathogenic.</div></div><div><h3>Conclusion</h3><div>These findings indicate that putative splicing variants represent a substantial portion of VUS in this clinical ES cohort, and most were identified in characterized LOF genes with RNA expression in blood. Integrating RNA analysis with clinical ES could clarify over 5% of reported VUS, even when accounting for known limitations in a rare disease setting, making it a viable strategy to increase diagnostic accuracy and the likelihood that a patient will receive a clinically meaningful report.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104369"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380403","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":"Expert opinion on facilitating intrafamily communication in rare diseases—Lessons from Fabry disease","authors":"Dominique P. Germain ,&nbsp;Fatma Al-Jasmi ,&nbsp;Gheona Altarescu ,&nbsp;Olga Azevedo ,&nbsp;Fellype C. Barreto ,&nbsp;Alessandro P. Burlina ,&nbsp;Fatih Ezgü ,&nbsp;Dawn A. Laney ,&nbsp;Ales Linhart ,&nbsp;Manish Maski ,&nbsp;Sergey Moiseev ,&nbsp;Dau-Ming Niu ,&nbsp;Kotaro Nochioka ,&nbsp;Yan Ouyang ,&nbsp;Huseyin Onay ,&nbsp;Mary Pavlou ,&nbsp;Nicholas Pachter ,&nbsp;Juan Politei ,&nbsp;Sunbul Rawda ,&nbsp;Richard P. Steeds ,&nbsp;Irina Maksimova","doi":"10.1016/j.gimo.2025.103481","DOIUrl":"10.1016/j.gimo.2025.103481","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103481"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926808","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":"Telethon Undiagnosed Disease Program: Structured approach to solving rare childhood-onset genetic diseases","authors":"Annalaura Torella ,&nbsp;Manuela Morleo ,&nbsp;Carmine Spampanato ,&nbsp;Raffaele Castello ,&nbsp;Mariateresa Zanobio ,&nbsp;Giulio Piluso ,&nbsp;Pasquale Di Letto ,&nbsp;Maria Elena Onore ,&nbsp;Sarah Iffat Rahman ,&nbsp;Francesco Musacchia ,&nbsp;Michele Pinelli ,&nbsp;Giuseppina Vitiello ,&nbsp;Giulia De Riso ,&nbsp;Angelo Selicorni ,&nbsp;Milena Mariani ,&nbsp;Cecilia Daolio ,&nbsp;Valeria Capra ,&nbsp;Marcello Scala ,&nbsp;Francesca Nardecchia ,&nbsp;Serena Galosi ,&nbsp;Antonio Trabacca","doi":"10.1016/j.gimo.2026.104394","DOIUrl":"10.1016/j.gimo.2026.104394","url":null,"abstract":"<div><h3>Purpose</h3><div>Many children with severe genetic disorders remain undiagnosed despite advanced genomic technologies. Early diagnosis is vital for prognosis, genetic counseling, and targeted treatment development. This study aims to increase diagnostic rates in complex pediatric cases and foster research into disease mechanisms.</div></div><div><h3>Methods</h3><div>Launched in 2016, the Telethon Undiagnosed Diseases Program provides a structured, multicenter approach to rare disease diagnosis. Standardized case submission criteria ensured consistent clinical data collection. Children with severe, multisystemic disorders and prior negative genetic tests were eligible. After case approval, trio-based exome sequencing was performed, with regular reanalysis for unsolved cases until December 2024.</div></div><div><h3>Results</h3><div>Between June 2016 and December 2023, 1338 cases were submitted by 60 clinicians from 22 Italian centers; 1019 were accepted. A definitive genetic diagnosis was achieved in 49% of cases, implicating 330 genes. Most pathogenic variants (70.2%) were de novo, reflecting demographic trends, such as delayed parenthood. The remainder included autosomal recessive or X-linked variants, with homozygosity observed in 9% of patients.</div></div><div><h3>Conclusion</h3><div>The Telethon Undiagnosed Diseases Program significantly shortened the average diagnostic odyssey of ∼8 years. Children born after 2016 benefited from faster diagnoses. This initiative offers a scalable, cost-effective model for improving diagnosis, guiding treatment, and supporting therapeutic innovation in rare pediatric diseases.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104394"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147706348","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":"Population-specific optimization of polygenic risk scores for breast cancer in East Asians","authors":"Shu-Hsuan Liu,&nbsp;Yu-Chun Wang,&nbsp;Yun-Jer Shieh,&nbsp;Hai-Feng Tan,&nbsp;Kuo-Jang Kao,&nbsp;Chih-Chiang Hung,&nbsp;Ming-Feng Hou,&nbsp;Chi-Cheng Huang,&nbsp;Ching-Hung Lin,&nbsp;An-Chieh Feng,&nbsp;Jeng-Fong Chiou,&nbsp;Chien-Hsiun Chen,&nbsp;Ling-Hui Li","doi":"10.1016/j.gimo.2026.104487","DOIUrl":"10.1016/j.gimo.2026.104487","url":null,"abstract":"<div><h3>Purpose</h3><div>Polygenic risk scores (PRS) have shown promise in predicting disease susceptibility, but their accuracy varies across populations due to the limited representation of non-European ancestries in genomic studies. While European-derived PRS demonstrate some transferability to Asian populations, optimizing these scores for specific populations remains crucial for improving risk prediction.</div></div><div><h3>Methods</h3><div>Using data from the Taiwan Precision Medicine Initiative (<em>n</em> = 46,422) and an external validation cohort (<em>n</em> = 891), we developed an approach to optimize European-derived PRS for breast cancer prediction in East Asians. Our method involved 2 key steps: (1) replacing European PRS variants with Asian-specific single nucleotide polymorphisms within the same linkage disequilibrium blocks (<em>r</em>² &gt; 0.8) and (2) incorporating additional population-specific variants. We validated this approach using both breast and prostate cancer data sets.</div></div><div><h3>Results</h3><div>The optimized PRS (PRS_{EUR_replace+TPMI}) showed improved predictive performance compared with the original European PRS (PRS_EUR) in our main cohort, with an increased area under the curve from 0.608 to 0.617 and odds ratios per SD from 1.47 (95% CI 1.36-1.60) to 1.51 (95% CI 1.39-1.63). Individuals in the top 5% of PRS_{EUR_replace+TPMI} demonstrated a 2.09-fold increased risk of developing breast cancer compared with those in the 40^th to 60^th percentile. External validation confirmed enhanced performance, and similar improvements were observed when this method was applied to prostate cancer prediction.</div></div><div><h3>Conclusion</h3><div>Our study presents a practical approach for optimizing European-derived PRS in non-European populations, which is particularly beneficial for populations with limited genetic data. As genetic data collection expands in these populations, this approach may help reduce health care disparities in the implementation of precision medicine.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104487"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148995375","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":"Clinical, cytogenetic, and molecular insights from 32 years of the Portuguese Fanconi anemia cohort","authors":"Jorge Diogo Da Silva,&nbsp;Cláudia Oliveira,&nbsp;Nádia Neto,&nbsp;Isabel Serra Nunes,&nbsp;Pedro Oliveira,&nbsp;Isabel Alonso,&nbsp;Ana Rita Soares,&nbsp;Paula Jorge,&nbsp;Beatriz Porto","doi":"10.1016/j.gimo.2026.104491","DOIUrl":"10.1016/j.gimo.2026.104491","url":null,"abstract":"<div><h3>Purpose</h3><div>Fanconi anemia (FA) is a rare monogenic chromosome breakage syndrome that presents with variable morphologic abnormalities and progressive bone marrow failure. Based on over 30 years of diagnostic experience, our main goal was to describe the Portuguese FA population and assess potential clinical and analytical phenotypic correlations with both molecular variants and chromosome instability (CI).</div></div><div><h3>Methods</h3><div>We evaluated the in-house database from the Cytogenetics Laboratory of the School of Medicine and Biomedical Sciences, University of Porto, which has provided nationwide CI testing since 1993.</div></div><div><h3>Results</h3><div>Ninety-three FA cases were diagnosed between January 1993 and October 2025; 1 was diagnosed in the prenatal setting due to severe malformations. Molecular characterization was available for 50 of these cases. Of these, 45 carried <em>FANCA</em> variants in homozygosity or compound heterozygosity, with 38% (of Romani ethnicity) harboring the homozygous NM_000135.4:c.295C&gt;T p.(Gln99Ter) founder variant. Five additional cases carried variants in <em>FANCD2, FANCG, FANCJ,</em> or <em>PALB2.</em> The most common clinical presentation comprised both hematologic and morphologic phenotypes, observed in 47% of cases. Isolated hematologic and morphologic presentations were observed in 27% and 13% of cases, respectively, while the remaining 13% of patients were asymptomatic.</div><div>Cytogenetic diagnosis using the standard 1,2,3,4-diepoxybutane test was extremely accurate. Follow-up cytogenetic assessments revealed likely somatic genetic reversals in 2 cases occurring years after the diagnosis, suggesting the importance of reevaluating the 1,2,3,4-diepoxybutane test. CI correlated significantly with the hematologic phenotype and red blood cell analytic parameters.</div></div><div><h3>Conclusion</h3><div>Our data allowed the characterization of the Portuguese FA cohort from clinical, cytogenetic, and molecular perspectives, including the identification of population-specific molecular findings and associations between CI and clinical features. Findings related to cytogenetic assessment proved useful not only for diagnosis but also for FA follow-up and prognostic purposes.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 104491"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148995371","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}