Genetics in Medicine最新文献

{"title":"Defining next steps in the clinical implementation of polygenic scores: A landscape analysis of professional groups’ perspectives","authors":"Rebecca Purvis ,&nbsp;Laura E. Forrest ,&nbsp;Mary-Anne Young ,&nbsp;Sharne Limb ,&nbsp;Paul James ,&nbsp;Natalie Taylor","doi":"10.1016/j.gim.2025.101414","DOIUrl":"10.1016/j.gim.2025.101414","url":null,"abstract":"<div><h3>Purpose</h3><div>Professional perspectives on polygenic scores (PGS) have surged in-line with significant research investment. It is unclear whether these perspectives are leading the health care sector toward a comprehensive implementation approach. This scoping review addresses this knowledge gap, analyzing available publications for concurring and discordant perspectives.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>A total of 28 perspectives were analyzed. Implementation was supportable if evidentiary thresholds for clinical utility could be met, with exceptions being in vitro fertilization and prenatal settings. Evidence base and relative advantage of PGS were the strongest determinants of implementation success, with resourcing also being emphasized. Key strategies included ongoing research, developing education materials, and facilitating relay of information. Attention was not paid to leadership nor to stakeholder interrelationships. There was no recommended framework to facilitate the clinical implementation of PGS.</div></div><div><h3>Conclusion</h3><div>The steps toward 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 utilizing implementation methodologies. Continuing efforts to establish PGS clinical utility and value, guidelines and policies, and educational materials are needed.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 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}

{"title":"Optimizing gene panels for equitable reproductive carrier screening: The Goldilocks approach","authors":"Mia J. Gruzin ,&nbsp;Matthew Hobbs ,&nbsp;Rachel E. Ellsworth ,&nbsp;Sarah Poll ,&nbsp;Sienna Aguilar ,&nbsp;Jaysen Knezovich ,&nbsp;Nicole Faulkner ,&nbsp;Nick Olsen ,&nbsp;Swaroop Aradhya ,&nbsp;Leslie Burnett","doi":"10.1016/j.gim.2025.101387","DOIUrl":"10.1016/j.gim.2025.101387","url":null,"abstract":"<div><h3>Purpose</h3><div>Professional organizations recommend pan-ancestry carrier screening for autosomal recessive and X-linked conditions. Advances in DNA sequencing have allowed the analysis of hundreds of genes; however, the optimal number of genes for carrier screening remains unclear. The American College of Medical Genetics and Genomics (ACMG) has proposed a tiered approach recommending screening for 113 genes.</div></div><div><h3>Methods</h3><div>We analyzed ClinVar and gnomAD v4.1.0, for genes associated with serious autosomal recessive and X-linked conditions and modeled screening performance across panels of varying compositions and sizes in diverse genetic ancestries. We also reevaluated the ACMG gene list using the updated gnomAD data.</div></div><div><h3>Results</h3><div>We identified potential inconsistencies in the ACMG gene lists, particularly in the carrier test performance (defined as a positive yield) for underrepresented genetic ancestry groups. Modeling of the population data for 1310 genes revealed that the screening of 152, 248, 531, and 725 genes achieved 90%, 95%, 99%, and 99.7% positive yields, respectively, in couples. Real-world data from the screening of more than 60,000 couples were used to validate the model.</div></div><div><h3>Conclusion</h3><div>Our methodology optimizes the gene content of carrier screening panels for diverse ancestry groups, provides a mechanism for continually updating guidelines, ensures consistency with genomic population data, and improves equity across populations.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101387"},"PeriodicalIF":6.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624279","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":"Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria","authors":"Timothy Bergquist ,&nbsp;Sarah L. Stenton ,&nbsp;Emily A.W. Nadeau ,&nbsp;Alicia B. Byrne ,&nbsp;Marc S. Greenblatt ,&nbsp;Steven M. Harrison ,&nbsp;Sean V. Tavtigian ,&nbsp;Anne O'Donnell-Luria ,&nbsp;Leslie G. Biesecker ,&nbsp;Predrag Radivojac ,&nbsp;Steven E. Brenner ,&nbsp;Vikas Pejaver","doi":"10.1016/j.gim.2025.101402","DOIUrl":"10.1016/j.gim.2025.101402","url":null,"abstract":"<div><h3>Purpose</h3><div>We previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to <em>Strong</em>. A new generation of tools using distinctive approaches has since been released, and these methods must be independently calibrated for clinical application.</div></div><div><h3>Methods</h3><div>Using our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by 3 new tools (AlphaMissense, ESM1b, and VARITY) and calibrated scores meeting each evidence strength.</div></div><div><h3>Results</h3><div>All 3 tools reached the <em>Strong</em> level of evidence for variant pathogenicity and <em>Moderate</em> for benignity, although sometimes for few variants. Compared with previously recommended tools, these yielded at best only modest improvements in the trade-offs between evidence strength and false-positive predictions.</div></div><div><h3>Conclusion</h3><div>At calibrated thresholds, 3 new computational predictors provided evidence for variant pathogenicity at similar strength to the 4 previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101402"},"PeriodicalIF":6.6,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624276","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":"Biallelic null variants in C19orf44 cause a unique late-onset retinal dystrophy phenotype characterized by patchy perifoveal chorioretinal atrophy","authors":"Miriam Ehrenberg ,&nbsp;Maayan Avraham ,&nbsp;Sandeep Sarma Asodu ,&nbsp;Abigail R. Moye ,&nbsp;Riccardo Sangermano ,&nbsp;Leah Rizel ,&nbsp;Tahleel Ali-Nasser ,&nbsp;Ifat Sher ,&nbsp;David Gurwitz ,&nbsp;Katherine R. Chao ,&nbsp;Antonio Rivera ,&nbsp;Andrew R. Webster ,&nbsp;Carlo Rivolta ,&nbsp;Hadas Newman ,&nbsp;Eran Pras ,&nbsp;Ygal Rotenstreich ,&nbsp;Eyal Banin ,&nbsp;Eric A. Pierce ,&nbsp;Dinah Zur ,&nbsp;Gavin Arno ,&nbsp;Tamar Ben-Yosef","doi":"10.1016/j.gim.2025.101401","DOIUrl":"10.1016/j.gim.2025.101401","url":null,"abstract":"<div><h3>Purpose</h3><div>To identify the genetic cause for disease in individuals affected with inherited retinal disease and to characterize their retinal phenotype and the properties of the underlying gene.</div></div><div><h3>Methods</h3><div>Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, visual field testing, fundus autofluorescence, optical coherence tomography, and electroretinography. Genetic analyses included exome, genome, and Sanger sequencing. Gene expression pattern was analyzed by reverse transcription-polymerase chain reaction. Localization of the encoded protein in cells and in the human retina was examined by immunofluorescence staining.</div></div><div><h3>Results</h3><div>Four different pathogenic variants in <em>C19orf44</em> were identified in 15 biallelic individuals from 11 unrelated families. The most common variant was c.549_550del p.(Ser185ProfsTer2). Most individuals were affected with a unique clinical phenotype characterized by late-onset patchy perifoveal chorioretinal atrophy and electroretinographic features of rod-cone degeneration. <em>C19orf44</em> is expressed in various human tissues, including the retina, where it was found in the outer nuclear layer and in the outer plexiform layer. In cultured cells (hTERT RPE-1 and HeLa) and in human primary fibroblasts, C19orf44 is found in the nucleus, and it is downregulated during mitosis.</div></div><div><h3>Conclusion</h3><div>Based on our results, <em>C19orf44</em> is crucial for normal human retinal function, and pathogenic variants in this gene are associated with autosomal recessive inherited retinal disease.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101401"},"PeriodicalIF":6.6,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624272","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":"Long-term follow-up of children who received rapid genomic sequencing","authors":"Erica Sanford Kobayashi ,&nbsp;Laura E. Tobin ,&nbsp;Madison Arenchild ,&nbsp;Wendy Benson ,&nbsp;Nicole G. Coufal ,&nbsp;Edwin F. Juarez ,&nbsp;Stephen F. Kingsmore ,&nbsp;Jason Knight ,&nbsp;Jerica Lenberg ,&nbsp;Adam Schwarz ,&nbsp;Ofelia Vargas-Shiraishi ,&nbsp;Kristen Wigby ,&nbsp;Matthew Bainbridge","doi":"10.1016/j.gim.2025.101403","DOIUrl":"10.1016/j.gim.2025.101403","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore long-term trajectories of children who received rapid genome sequencing (RGS) in intensive care settings.</div></div><div><h3>Methods</h3><div>We examined the electronic health records of 67 critically ill pediatric patients who received RGS 6 to 8 years ago with a collective initial diagnostic yield of 46%.</div></div><div><h3>Results</h3><div>The median length of follow-up was 6.2 years (interquartile range 4.0-7.2 years). RGS-diagnosed patients had a longer average follow-up time compared with undiagnosed patients (5.9 years vs 4.8 years, <em>P</em> = .026) and more subspecialty appointments per follow-up year (9.4 vs 6.9, <em>P</em> = .036). Mortality during the follow-up period was 9%. Patients averaged 2.1 hospital readmissions per follow-up year and 28.1 hospitalized days per follow-up year. Forty-four patients (66%) had a documented new phenotype in the electronic health records during their follow-up period. Seven patients received clinician-driven reanalysis during the follow-up period, yielding 1 new diagnosis. Systematic reanalysis of RGS performed as part of this study identified 4 new candidate diagnoses.</div></div><div><h3>Conclusion</h3><div>Pediatric patients who receive RGS during intensive care unit hospitalizations continue to be high health care utilizers in subsequent years, regardless of whether RGS identified a diagnosis. Additionally, two-thirds of this cohort had a documented phenotypic change over the follow-up period, indicating dynamic clinical evolution in the years after RGS.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101403"},"PeriodicalIF":6.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585446","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":"Addendum: Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)","authors":"Ting Wen,&nbsp;M. Katharine Rudd,&nbsp;Melanie A. Manning,&nbsp;ACMG Professional Practice and Guidelines Committee","doi":"10.1016/j.gim.2024.101335","DOIUrl":"10.1016/j.gim.2024.101335","url":null,"abstract":"<div><div>This document was reaffirmed by the ACMG Board of Directors as of 26 August 2024 with the following addendum:</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101335"},"PeriodicalIF":6.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}