Genetics in Medicine最新文献

{"title":"Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases.","authors":"Klaus Schmitz-Abe, Qifei Li, Sunny Greene, Michela Borrelli, Shiyu Luo, Madesh C Ramesh, Pankaj B Agrawal","doi":"10.1016/j.gim.2025.101413","DOIUrl":"10.1016/j.gim.2025.101413","url":null,"abstract":"<p><strong>Purpose: </strong>Publicly available genomic databases are critical in understanding human genetic variation. They also provide unique insights into patterns of genetic constraints and their relationship with human disease.</p><p><strong>Methods: </strong>We utilized one of the largest publicly available databases, gnomAD, to determine genes that are highly constrained for only loss of function (LoF), only missense, and both LoF/missense variants. We identified their unique signatures and explored their causal relationship with human diseases. Those genes were also evaluated for chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases.</p><p><strong>Results: </strong>We identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways for those constrained genes associated with human disease. In addition, we identified genes that are currently not known to cause human disease, which may be excellent gene discovery candidates.</p><p><strong>Conclusions: </strong>We elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins. The findings can also advance research in rare diseases.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101413"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691989","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":"Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa.","authors":"Lorenzo Bianco, Julien Navarro, Christelle Michiels, Riccardo Sangermano, Christel Condroyer, Aline Antonio, Alessio Antropoli, Camille Andrieu, Emily M Place, Eric A Pierce, Said El Shamieh, Vasily Smirnov, Vasiliki Kalatzis, Luke Mansard, Anne-Françoise Roux, Béatrice Bocquet, José-Alain Sahel, Isabelle Meunier, Kinga M Bujakowska, Isabelle Audo, Christina Zeitz","doi":"10.1016/j.gim.2025.101418","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101418","url":null,"abstract":"<p><strong>Purpose: </strong>Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss rod and cone photoreceptors, leading to visual impairment and blindness. To date, X-linked RP has been associated with variants in three genes (RPGR, RP2, OFD1), while genetic defects at three loci (RP6, RP24, RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP.</p><p><strong>Methods: </strong>Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at three referral centers. Specifically, two probands were identified at the National Reference Centre for Rare Retinal Diseases REFERET (Paris, France), two at Massachusetts Eye and Ear Hospital (Boston, MA, USA), and one at the National Reference Centre for Inherited Sensory Diseases MAOLYA (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays.</p><p><strong>Results: </strong>We identified four rare single nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, as well as a complete gene deletion, in five unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly though partial loss of enzymatic activity and mitochondrial function.</p><p><strong>Conclusions: </strong>Our findings suggest that variants in IDH3G are a novel cause of X-linked RP, possibly by impairing mitochondrial function and ultimately resulting in photoreceptor degeneration.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101418"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676897","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":"Clinical signatures of SYNGAP1-related disorders through data integration.","authors":"Jillian L McKee, Jan H Magielski, Julie Xian, Stacey Cohen, Jonathan Toib, Alicia Harrison, Chen Chen, Dan Kim, Aakash Rathod, Elise Brimble, Nasha Fitter, J Michael Graglia, Kathryn A Helde, Sarah McKeown Ruggiero, Michael J Boland, Benjamin L Prosser, Rob Sederman, Ingo Helbig","doi":"10.1016/j.gim.2025.101419","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101419","url":null,"abstract":"<p><strong>Purpose: </strong>SYNGAP1 is a genetic neurodevelopmental disorder characterized by generalized epilepsy, autism, and intellectual disability. Despite a comparatively high prevalence, the longitudinal landscape remains relatively unexplored, and complete characterization is essential for clinical trial readiness.</p><p><strong>Methods: </strong>We combined electronic medical record data (n=158) with insurance claims data (n=246) to evaluate longitudinal progression of symptoms.</p><p><strong>Results: </strong>Phenotypes associated with SYNGAP1 included behavioral abnormalities (Odds ratio (OR) 12.35, 95% CI 9.21-16.78), generalized-onset seizures (OR 1.56, CI 1.20-2.02), autism (OR 12.23, CI 9.29-16.24), and a developmental profile with prominent deficits in verbal skill acquisition. Several clinical features showed distinct age-related patterns, such as a more than five-fold risk of autistic behavior emerging between 27 and 30 months. Generalized-onset seizures were significantly increased (OR 4.05, CI 2.02-7.59) after 3 years of age and persisted over time. Valproic acid and clobazam were commonly used for epilepsy treatment, while risperidone, aripiprazole, and guanfacine were commonly used for behavior management. Valproate and lamotrigine were more effective at reducing seizure frequencies or maintaining seizure freedom than other anti-seizure medications.</p><p><strong>Conclusion: </strong>We delineated the seizure, developmental, and behavioral trajectories in SYNGAP1-related disorders, to improve diagnosis, prognosis, and clinical care, as well as facilitating clinical trial readiness.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101419"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676864","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":"Primary Care Providers' Perspectives on Receiving Opportunistic Genomic Results from a National Study - the Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study.","authors":"Anna L Johannsen, Morgan E Danowski, Kailyn E Sitter, Charlene L Preys, Haley L Gerety, Charles A Brunette, Kurt D Christensen, J Michael Gaziano, Joshua W Knowles, Sumitra Muralidhar, Amy C Sturm, Yan V Sun, Stacey B Whitbourne, Thomas Yi, Jason L Vassy","doi":"10.1016/j.gim.2025.101416","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101416","url":null,"abstract":"<p><strong>Background: </strong>Patients are increasingly obtaining genetic health information and integrating it into their care with the help of their primary care provider (PCP). However, PCPs may not be adequately prepared to effectively utilize genetic results. Across the Veterans Health Administration (VA) health system, the Million Veteran Program Return Of Actionable Results-Familial Hypercholesterolemia (MVP-ROAR-FH) Study clinically confirms and returns genetic results associated with familial hypercholesterolemia (FH), identified in a national biobank program.</p><p><strong>Methods: </strong>PCPs who received their patient's genetic results through the MVP-ROAR-FH study were invited to participate in semi-structured interviews, which explored PCPs' familiarity with FH, how the results impacted medical management, and suggestions for process improvement. Interviews were transcribed and analyzed using directed content analysis and constant comparison methods to identify key themes.</p><p><strong>Results: </strong>Interviews with nine PCPs revealed varied levels of familiarity with genetic testing and FH. Most PCPs did not distinguish FH from common high cholesterol issues and already used similar treatment approaches. Many PCPs did not recall receiving results from the MVP-ROAR-FH study. Alerts in medical records were deemed effective for communicating results. PCPs valued genetics in informing patient care and identifying at-risk family members but noted several implementation barriers, such as additional workload and unclear medical management benefits. Recommendations for improving results disclosure included simplifying the genetic testing report and associated support documents.</p><p><strong>Conclusion: </strong>The study represents the first investigation into PCPs' experiences with receiving genetic test results from a biobank linked to a national healthcare system. Results suggest that PCPs generally view genetic testing as beneficial, though they may not significantly alter medical management. PCPs expressed that integrating genetics into routine care may be burdensome and require additional training, which may not be practical. The study underscores the need for accessible genetic information, which could be aided by specialized support roles or different clinical specialties assisting with incorporating genetic results into patient care.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101416"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691986","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":"Financial Assistance Programs for Genetic Testing: Effective, Ethical, and Sustainable Pathways to Improving Access Disparities?","authors":"Emily Hammad Mrig, Kathryn A Phillips, Mark Schlesinger","doi":"10.1016/j.gim.2025.101417","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101417","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101417"},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676891","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":"Systematic Method for Classifying Multiple Congenital Anomaly Cases in Electronic Health Records.","authors":"Elly Brokamp, Tyne Miller-Fleming, Alexandra Scalici, Gillian Hooker, Rizwan Hamid, Digna Velez Edwards, Wendy Chung, Yuan Luo, Krzysztof Kiryluk, Nita A Limidi, Nikhil K Khankari, Nancy J Cox, Lisa Bastarache, Megan M Shuey","doi":"10.1016/j.gim.2025.101415","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101415","url":null,"abstract":"<p><strong>Purpose: </strong>Congenital anomalies (CAs) affect ∼3% of live births and are the leading cause of infant morbidity and mortality. Many individuals have multiple congenital anomalies (MCA), a constellation of two or more unrelated CAs, yet there is no consensus on how to systematically identify these individuals in electronic health records (EHR). We developed a scalable method to characterize MCA in the EHR, allowing for the dramatic improvement of our understanding of the genetic and epidemiological underpinnings of MCA.</p><p><strong>Methods: </strong>From Vanderbilt University Medical Center's anonymized EHR database, we evaluated three different approaches for classifying MCA, including a novel approach that removed \"minor vs. major\" differentiation and their associated clinical utilization and population characteristics. Using phenome-wide association studies, we assessed the phenome associated with previously classified \"minor\" CAs.</p><p><strong>Results: </strong>Our proposed universal method for MCA identification in the EHR is accurate (PPV= 97.1%), associated with heightened hospital utilization (41% receiving inpatient care), and captures granular patterns of CAs. A secondary application of our method was done in two separate cohorts.</p><p><strong>Conclusion: </strong>We developed a method to comprehensively identify individuals with MCA in the EHR, allowing researchers to better investigate the genetic etiologies of MCA. This method can be applied across EHR databases with billing codes.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101415"},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673827","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":"Defining next steps in the clinical implementation of polygenic scores: A landscape analysis of professional groups' perspectives.","authors":"Rebecca Purvis, Laura E Forrest, Mary-Anne Young, Sharne Limb, Paul James, Natalie Taylor","doi":"10.1016/j.gim.2025.101414","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101414","url":null,"abstract":"<p><strong>Purpose: </strong>Professional perspectives on polygenic risk scores (PGS) have surged in-line with significant research investment. It is unclear whether these perspectives are leading the healthcare sector toward a comprehensive implementation approach. This scoping review addresses this knowledge gap, analysing available publications for concurring and discordant perspectives.</p><p><strong>Methods: </strong>Methodology followed the Arksey and O'Malley framework. Six databases were systematically searched alongside screening of professional websites. Descriptive and deductive content analyses were completed using the Consolidated Framework for Implementation Research and the Expert Recommendations for Implementing Change compilation.</p><p><strong>Results: </strong>28 perspectives were analysed. Implementation was supportable if evidentiary thresholds for clinical utility could be met, with exceptions being in-vitro fertilisation and prenatal settings. Evidence-base and relative advantage of PGS were the strongest determinants of implementation success, with resourcing also emphasised. Key strategies included ongoing research, developing education materials, and facilitating relay of information. Attention was not paid to leadership, nor to stakeholder inter-relationships. There was no recommended framework to facilitate the clinical implementation of PGS.</p><p><strong>Conclusion: </strong>The steps towards executing implementation remain vague. Commonalities in perspectives suggest value in a transferable approach. If PGS are to be successful, policy makers and leaders must consider effective resource allocation by addressing priority barriers and utilising implementation methodologies. Continuing efforts to establish PGS clinical utility and value, guidelines and policies, and educational materials are needed.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101414"},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673826","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":"Correspondence on \"Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort\" by Akter et al.","authors":"Fowzan S Alkuraya","doi":"10.1016/j.gim.2025.101388","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101388","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101388"},"PeriodicalIF":6.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656920","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":"Response to Alkuraya.","authors":"Hosneara Akter, Nasna Nassir, Mohammed Uddin","doi":"10.1016/j.gim.2025.101389","DOIUrl":"10.1016/j.gim.2025.101389","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101389"},"PeriodicalIF":6.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624287","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":"Insulin receptor variants: extending the traditional Mendelian spectrum.","authors":"Delphine Collin-Chavagnac, Cécile Saint-Martin, Lotfi Bedidi, Louis Lebreton, Vahid Aslanzadeh, Corinne Vigouroux, Christine Bellanné-Chantelot, Robert K Semple, Olivier Lascols, Isabelle Jéru","doi":"10.1016/j.gim.2025.101404","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101404","url":null,"abstract":"<p><strong>Purpose: </strong>INSR encodes the insulin receptor, the essential entrainer of growth and metabolism to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR) syndromes, namely type A insulin resistance, Rabson-Mendenhall (RMS), and Donohue (DS) syndromes. However, no large cohort studies focused on variant classification and its diagnostic value have been described.</p><p><strong>Methods: </strong>This multicentric cohort study included 73 patients carrying INSR variants, referred for IR by 52 centers from six countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms, and the American College of Medical Genetics and Genomics (ACMG) guidelines.</p><p><strong>Results: </strong>Besides expanding the INSR mutational spectrum, this study suggested a semi-dominant inheritance in several DS/RMS families. Questioning strictly Mendelian inheritance, heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a higher LoF frequency in IR patients than in the general population (OR: 5.77). Diagnostic challenges arose when trying to refine classification criteria for variants of uncertain significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense outperformed REVEL.</p><p><strong>Conclusion: </strong>The spectrum of INSR-related disorders extends beyond traditional entities. Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration and functional assays are needed to drive precision medicine forward.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101404"},"PeriodicalIF":6.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648338","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}