Genetics in Medicine最新文献

{"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 ,&nbsp;Julien Navarro ,&nbsp;Christelle Michiels ,&nbsp;Riccardo Sangermano ,&nbsp;Christel Condroyer ,&nbsp;Aline Antonio ,&nbsp;Alessio Antropoli ,&nbsp;Camille Andrieu ,&nbsp;Emily M. Place ,&nbsp;Eric A. Pierce ,&nbsp;Said El Shamieh ,&nbsp;Vasily Smirnov ,&nbsp;Vasiliki Kalatzis ,&nbsp;Luke Mansard ,&nbsp;Anne-Françoise Roux ,&nbsp;Béatrice Bocquet ,&nbsp;José-Alain Sahel ,&nbsp;Isabelle Meunier ,&nbsp;Kinga M. Bujakowska ,&nbsp;Isabelle Audo ,&nbsp;Christina Zeitz","doi":"10.1016/j.gim.2025.101418","DOIUrl":"10.1016/j.gim.2025.101418","url":null,"abstract":"<div><h3>Purpose</h3><div>Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (<em>RPGR</em>, <em>RP2</em>, and <em>OFD1</em>), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP.</div></div><div><h3>Methods</h3><div>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 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays.</div></div><div><h3>Results</h3><div>We identified 4 rare single-nucleotide variants in <em>IDH3G</em> (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 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. <em>IDH3G</em> encodes the <em>γ</em> 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 <em>IDH3A</em> and <em>IDH3B,</em> 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 through partial loss of enzymatic activity and mitochondrial function.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that variants in <em>IDH3G</em> are a novel cause of X-linked RP.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 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 ,&nbsp;Jan H. Magielski ,&nbsp;Julie Xian ,&nbsp;Stacey Cohen ,&nbsp;Jonathan Toib ,&nbsp;Alicia Harrison ,&nbsp;Chen Chen ,&nbsp;Dan Kim ,&nbsp;Aakash Rathod ,&nbsp;Elise Brimble ,&nbsp;Nasha Fitter ,&nbsp;J. Michael Graglia ,&nbsp;Kathryn A. Helde ,&nbsp;Sarah McKeown Ruggiero ,&nbsp;Michael J. Boland ,&nbsp;Benjamin L. Prosser ,&nbsp;Rob Sederman ,&nbsp;Ingo Helbig","doi":"10.1016/j.gim.2025.101419","DOIUrl":"10.1016/j.gim.2025.101419","url":null,"abstract":"<div><h3>Purpose</h3><div><em>SYNGAP1</em> 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.</div></div><div><h3>Methods</h3><div>We combined electronic medical record data (<em>n</em> = 158) with insurance claims data (<em>n</em> = 246) to evaluate longitudinal progression of symptoms.</div></div><div><h3>Results</h3><div>Phenotypes associated with <em>SYNGAP1</em> included behavioral abnormalities (odds ratio [OR]: 12.35, 95% CI: 9.21-16.78), generalized-onset seizures (OR: 1.56, 95% CI: 1.20-2.02), autism (OR: 12.23, 95% 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 5-fold risk of autistic behavior emerging between 27 and 30 months. Generalized-onset seizures were significantly increased (OR: 4.05, 95% CI: 2.02-7.59) after 3 years of age and persisted over time. Valproic acid and clobazam were commonly used for epilepsy treatment, whereas 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 antiseizure medications.</div></div><div><h3>Conclusion</h3><div>We delineated the seizure, developmental, and behavioral trajectories in <em>SYNGAP1-</em>related disorders, to improve diagnosis, prognosis, and clinical care, and facilitating clinical trial readiness.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 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 ,&nbsp;Morgan E. Danowski ,&nbsp;Kailyn E. Sitter ,&nbsp;Charlene L. Preys ,&nbsp;Haley L. Gerety ,&nbsp;Charles A. Brunette ,&nbsp;Kurt D. Christensen ,&nbsp;J. Michael Gaziano ,&nbsp;Joshua W. Knowles ,&nbsp;Sumitra Muralidhar ,&nbsp;Amy C. Sturm ,&nbsp;Yan V. Sun ,&nbsp;Stacey B. Whitbourne ,&nbsp;Thomas Yi ,&nbsp;The VA Million Veteran Program,&nbsp;Jason L. Vassy","doi":"10.1016/j.gim.2025.101416","DOIUrl":"10.1016/j.gim.2025.101416","url":null,"abstract":"<div><h3>Purpose</h3><div>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 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.</div></div><div><h3>Methods</h3><div>PCPs who received their patient’s genetic results through the MVP-ROAR-FH study were invited to participate in semistructured interviews, which explored PCPs’ familiarity with FH, how the results affected medical management, and suggestions for process improvement. Interviews were transcribed and analyzed using directed content analysis and constant comparison methods to identify key themes.</div></div><div><h3>Results</h3><div>Interviews with 9 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.</div></div><div><h3>Conclusion</h3><div>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, although 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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 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 ,&nbsp;Kathryn A. Phillips ,&nbsp;Mark Schlesinger","doi":"10.1016/j.gim.2025.101417","DOIUrl":"10.1016/j.gim.2025.101417","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 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 ,&nbsp;Cécile Saint-Martin ,&nbsp;Lotfi Bedidi ,&nbsp;Louis Lebreton ,&nbsp;Vahid Aslanzadeh ,&nbsp;Corinne Vigouroux ,&nbsp;Christine Bellanné-Chantelot ,&nbsp;Robert K. Semple ,&nbsp;Olivier Lascols ,&nbsp;Isabelle Jéru","doi":"10.1016/j.gim.2025.101404","DOIUrl":"10.1016/j.gim.2025.101404","url":null,"abstract":"<div><h3>Purpose</h3><div><em>INSR</em> encodes the insulin receptor, the essential entrainer of growth and metabolism to nutritional cues. <em>INSR</em> variants cause a spectrum of monogenic insulin resistance (IR) syndromes, namely, type A insulin resistance, Rabson-Mendenhall, and Donohue syndromes. However, to our knowledge, no large cohort studies focused on variant classification and its diagnostic value have been described.</div></div><div><h3>Methods</h3><div>This multicentric cohort study included 73 patients carrying <em>INSR</em> variants, referred for IR by 52 centers from 6 countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms and the American College of Medical Genetics and Genomics guidelines.</div></div><div><h3>Results</h3><div>Besides expanding the <em>INSR</em> mutational spectrum, this study suggested a semidominant inheritance in several Donohue/Rabson-Mendenhall syndrome 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 (odds ratio 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.</div></div><div><h3>Conclusion</h3><div>The spectrum of <em>INSR</em>-related disorders extends beyond traditional entities. Heterozygous <em>INSR</em> LoF variants may increase IR susceptibility. International collaboration and functional assays are needed to drive precision medicine forward.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 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}

{"title":"Pegvaliase therapy for phenylketonuria: Real-world safety, efficacy, and medication access outcomes in a pharmacist-led pegvaliase program","authors":"Sofia Shrestha ,&nbsp;Alicia L. Zagel ,&nbsp;Nishitha R. Pillai ,&nbsp;Alia Ahmed ,&nbsp;Jenny Jacobson ,&nbsp;Alicia Ranasinghe ,&nbsp;Chester B. Whitley ,&nbsp;Jeanine R. Jarnes","doi":"10.1016/j.gim.2025.101405","DOIUrl":"10.1016/j.gim.2025.101405","url":null,"abstract":"<div><h3>Purpose</h3><div>Given the complexity and close monitoring needs of pegvaliase, we evaluated the real-life clinical outcomes of patients with phenylketonuria (PKU) managed in a pharmacist-led pegvaliase pharmacotherapy program.</div></div><div><h3>Methods</h3><div>A review of 51 PKU patients initiated on pegvaliase at the PKU clinic of M Health Fairview, Minneapolis, MN, between May 2018 and May 2024 was conducted. Data collected included baseline characteristics, payer authorization outcomes, treatment history, phenylalanine (Phe) levels, adverse events, and management strategies.</div></div><div><h3>Results</h3><div>At 12-months, 55% of patients achieved Phe goal (360 μmol/L), increasing to 77% at 24 months. Among patients on maintenance doses, 87% achieved ≥20% Phe reduction at 12 months, rising to 93.5% at 24 months. Combination therapy with sapropterin and pegvaliase was associated with faster Phe goal attainment compared with pegvaliase monotherapy (<em>P</em> = .0599). Anaphylaxis occurred in 31% of patients, predominantly during the maintenance phase. All patients successfully initiated therapy without access barriers, although 35% required appeals for insurance approval. Common adverse events included injection site reactions (90%) and arthralgia (69%). Special populations, including 1 adolescent and 2 pregnant women, were safely managed on pegvaliase.</div></div><div><h3>Conclusion</h3><div>Pegvaliase effectively reduced Phe levels in PKU patients, although it carried significant risks of anaphylaxis and other adverse events. A pharmacist-led program and interdisciplinary collaboration was crucial for prompt access and effective management.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101405"},"PeriodicalIF":6.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648397","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}