Genetics in Medicine最新文献

{"title":"Reporting ABCD1 Variants as Actionable Secondary Findings on Exome and Genome Sequencing.","authors":"Carlos A Dominguez Gonzalez, Nancy B Spinner, Rebecca C Ahrens-Nicklas, Lisa R Young, Laura A Voss, Sara L Reichert, Daniel J Gallo, Julie S Cohen, Joshua L Bonkowsky, Stephanie R Keller, Mariko L Bennett, Amy M Pizzino, Meghan Swantkowski, Kaley Arnold, Jamie L Fraser, Felicity J Emerson, Kelly Miettunen, Ali Fatemi, Keith P Van Haren, Laura Adang, Amy Waldman, Lisa Emrick, Florian Eichler, Adeline Vanderver","doi":"10.1016/j.gim.2025.101425","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101425","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101425"},"PeriodicalIF":6.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811066","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":"Estimation of the number of people with Down syndrome living in Canada.","authors":"Gert de Graaf, Laura LaChance, Frank Buckley, Brian G Skotko","doi":"10.1016/j.gim.2025.101422","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101422","url":null,"abstract":"<p><strong>Purpose: </strong>We estimate the live births (LBs), selective terminations, miscarriages, and overall population with Down syndrome (DS) in Canada from 1950-2020. This study adds to previous work from the United States, Europe, Australia, and New Zealand.</p><p><strong>Method: </strong>The LBs with DS-in the absence of DS-related terminations-were estimated on the maternal age distribution in the general population. Actual LBs were modeled on registry data. We applied constructed survival curves to annual LBs to estimate population numbers.</p><p><strong>Results: </strong>In 2020, there were an estimated 418 LBs with DS in Canada. As a result of DS-related elective terminations, there were 54% fewer children with DS born than potentially could have been born in Canada, as of 2020. The estimated number of people with DS in Canada has increased from 5,138 people in 1950 to 22,367 in 2020.</p><p><strong>Conclusion: </strong>Whereas, in recent years, the population size of people with DS is decreasing in Australia, New Zealand, and Europe, the number of people with DS is still growing in the United States and Canada. In Canada, however, the growth rate is increasingly slowing down, probably foreshadowing a population contraction in the coming years.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101422"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803092","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":"Outcomes and effectiveness of decision aids for families affected by hereditary cancer syndromes: A scoping review.","authors":"Sun-Young Park, Youlim Kim, Maria C Katapodi, Yeon-Joo Kim, Heejung Chae, Yoon-Jung Choi, Kum Hei Ryu, Eun-Gyeong Lee, Sun-Young Park, Youlim Kim, Maria C Katapodi, Yeon-Joo Kim, Heejung Chae, Yoon-Jung Choi, Kum Hei Ryu, Eun-Gyeong Lee, Sun-Young Kong, So-Youn Jung","doi":"10.1016/j.gim.2025.101424","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101424","url":null,"abstract":"<p><strong>Objective: </strong>In the past 15 years, numerous decision aids (DAs) have been developed to assist families affected by hereditary cancer syndromes in decision-making for managing inheritance and cancer risk. We identified the range and characteristics of DAs, focusing on their development stage according to guideline recommendations, their outcomes, and effectiveness.</p><p><strong>Methods: </strong>A comprehensive search was conducted in MEDLINE, EMBASE, Cochrane, CINAHL, and PsycINFO, along with manual searches. Eligible articles reported DAs for supporting families affected by hereditary cancer syndromes, published in English from inception to July 2024. Quality was assessed using the Mixed Methods Appraisal Tool.</p><p><strong>Results: </strong>From 15,066 records, 32 studies with a moderate risk of bias, reporting 23 unique DAs, were identified. Most DAs targeted women (69.6%) with hereditary breast and ovarian cancer syndrome (73.9%) in North America and Europe (81.3%), primarily supporting decisions on cancer risk-reduction strategies (56.5%) and genetic testing/counseling (47.8%). Only four DAs were consistent with guideline-recommended development process, including prototype development, alpha- and beta-testing. Development and alpha-testing outcomes included user experience, understandability, and psychological impact. Beta-testing evaluated decision-making capacity, quality of the decision-making process, psychological impact, and impact on decisions. DAs consistently improved decision-making capacity and quality of the decision-making process but showed variable effects on psychological outcomes and actual decision in risk-management.</p><p><strong>Conclusion: </strong>DAs are under-developed for genetic, racial, or gender minorities, according to guideline-recommended development process. Future research should develop DAs for broader populations and clarify their effectiveness, particularly regarding psychological outcomes.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101424"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803097","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":"The development and evaluation of Polygenic Risk Score reports: A systematised review of the literature.","authors":"Mia Hanley, Sharne Limb, Rebecca Purvis, Sibel Saya, Paul A James, Laura Elenor Forrest","doi":"10.1016/j.gim.2025.101426","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101426","url":null,"abstract":"<p><strong>Purpose: </strong>The return of polygenic risk scores (PGS) is currently being assessed in research settings for clinical utility and validity, and it is anticipated that PGS will soon be implemented in a clinical setting. There are limited guidelines regarding PGS communication and reporting, thus there is a need to identify and analyse the current research to determine the most acceptable means of presenting PGS results through reports. The aim of this review is to examine the literature regarding the development and evaluation of PGS communication tools, including risk reports, visual aids, and online tools.</p><p><strong>Methods: </strong>Research studies that evaluated preferences, understanding or interpretation of PGS through a report, visual aid or tool were included. The search strategy was applied to MEDLINE (via Ovid) and APA PsychInfo.</p><p><strong>Results: </strong>Thirteen studies met the inclusion criteria. The presentation of PGS differed across studies, including icon arrays and bell curves for visual presentation, and absolute risk, relative risk, and genetic risk score for numerical presentation. Participants' understanding of PGS differed between studies. Studies supported using absolute risk and avoiding stigmatising colours to communicate results.</p><p><strong>Conclusion: </strong>To support PGS clinical implementation, the development of an evidence based PGS report evaluated by consumers and various healthcare professionals is needed.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101426"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803099","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":"A Literature Review and Pooled Case Analysis of Cardiofaciocutaneous Syndrome to Estimate Cancer Risk.","authors":"Jazmyn Bess, Toniya Brown, Sonia Bhala, Anaqa Faizer, Muzzammil Ahmadzada, Alicia A Livinski, Alex Pemov, Jung Kim, Philip S Rosenberg, Gina M Ney, Douglas R Stewart","doi":"10.1016/j.gim.2025.101423","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101423","url":null,"abstract":"<p><strong>Purpose: </strong>We quantified cancer risk in cardiofaciocutaneous syndrome (CFC), a rare RASopathy.</p><p><strong>Methods: </strong>From a comprehensive search, we reviewed articles from five databases and abstracted CFC cases with a clinical and/or molecular diagnosis to form a retrospective cohort. We collected information on BRAF, KRAS, MAP2K1, and MAP2K2 genetic variants when available. Genotype-phenotype (cancer) correlations, standardized incidence ratios (SIR) with age stratification, cumulative incidence and cause-specific hazard rates for cancer and cancer-free in CFC were calculated. A sensitivity analysis with molecular diagnoses only was also performed.</p><p><strong>Results: </strong>This study included 198 publications reporting 690 individuals. Only 1.6% (11) had cancer, including acute lymphoblastic leukemia (ALL). Six individuals had cancer and harbored pathogenic variants within BRAF, MAP2K1, and MAP2K2. Cumulative incidence by age 10 was 5% for cancer or cancer-free death. Hazard Ratio (death) was 1-2% until age 3 and declined thereafter. Significant SIRs were found for all sites (SIR=4.96) and ALL (SIR=24.23).</p><p><strong>Conclusions: </strong>This is the largest investigation of cancer in CFC to date. Cancer risk in the CFC population was elevated but appears to be limited to younger than age three. However, modest case and cancer numbers limit accurate assessments of cancer risk in CFC and more studies are needed.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101423"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803091","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":"No association between FMR1 premutation and either ADHD or anxiety in 53,707 women undergoing genetic testing for family planning purposes.","authors":"Liraz Klausner, Shai Carmi, Shay Ben-Shachar, Noa Lev-El Halabi, Lina Basel-Salmon, Dana Brabbing Goldstein","doi":"10.1016/j.gim.2025.101428","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101428","url":null,"abstract":"<p><strong>Purpose: </strong>FMR1 premutation has been inconsistently associated with neuropsychiatric phenotypes, possibly due to ascertainment bias. We investigated the association between FMR1 premutation and attention deficit hyperactivity disorder (ADHD), anxiety, and other psychiatric disorders in large-scale population-based genetic carrier screening data.</p><p><strong>Methods: </strong>We defined premutation as having 58-200 CGG repeats. Phenotypes were identified in linked electronic medical records via formal diagnoses or relevant medication purchases. As a positive control, we assessed premature ovarian insufficiency (POI) and elevated follicle-stimulating hormone (FSH) levels before the age of 40.</p><p><strong>Results: </strong>Our study included 53,707 women, among them 464 premutation heterozygotes. The premutation status was associated with POI (hazard ratio [HR]: 4.08, 95% confidence interval [CI]: 2.16-7.72) and high FSH (HR: 3.43, 95% CI: 2.65-4.43) but not with ADHD (HR: 1.08; 95% CI: 0.75-1.56), anxiety (HR: 0.74; 95% CI: 0.53-1.04), anxiety and depression (HR: 0.86; 95% CI: 0.69-1.07), and other psychiatric disorders (HR: 1.22; 95% CI: 0.73-2.03). Our study was sufficiently powered to detect HR in the range approximately 1.5-2.</p><p><strong>Discussion: </strong>No association was found between FMR1 premutation status and either ADHD or anxiety. While our study design avoided bias towards affected families, participants may be healthier than average, and small effects cannot be excluded.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101428"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803094","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":"Non-coding single nucleotide and structural variants affecting the EYS putative promoter cause autosomal recessive retinitis pigmentosa.","authors":"Tamar Hayman, Shai Ovadia, Jaya Krishnan, Manon Bouckaert, Daan M Panneman, Milton English, Johanna Valensi, Frans P M Cremers, Tamar Ben Yosef, L Ingeborgh van den Born, Suzanne E de Bruijn, Susanne Roosing, Eyal Banin, Samer Khateb, Ruth Ashery-Padan, Frauke Coppieters, Anand Swaroop, Dror Sharon","doi":"10.1016/j.gim.2025.101427","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101427","url":null,"abstract":"<p><strong>Introduction: </strong>Variants in untranslated genomic regions are difficult to identify as pathogenic but are capable of causing disease by interfering with gene expression. This study aimed to characterize the effect of variants identified in the 5'-untranslated region of EYS in patients with autosomal recessive retinitis pigmentosa (ARRP).</p><p><strong>Methods: </strong>Variant screening included gene panels, Sanger, exome and genome sequencing. Functional validation included an electrophoretic mobility shift assay (EMSA) and various luciferase assays.</p><p><strong>Results: </strong>Patients with RP from six EYS biallelic Arab-Muslim families harbored a 5' noncoding EYS variant, c.-453G>T, and four harbored a structural variant affecting the 5' noncoding exons. EMSA analysis revealed an effect on binding of transcription factors for c.-453G>T and a neighboring variant c.-454G>T. Dual luciferase assays using overexpression of various transcription factors showed distinct effects on expression. c.-453G>T was associated with higher luciferase expression with CRX overexpression and c.-454G>C with OTX2 overexpression. In addition, the two variants were found to influence translation by affecting upstream initiation codons. Interestingly, visual function of EYS RP patients who harbor c.-453G>T are better than those with biallelic null EYS variants.</p><p><strong>Discussion: </strong>Our analysis revealed both single nucleotide and structural variants in the EYS promoter as the cause of ARRP. These variants may affect EYS expression via a dual mechanism by altering transcription factor binding affinity at the EYS promoter and by affecting upstream open reading frames.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101427"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795088","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":"Biochemical testing for congenital disorders of glycosylation: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Patricia L. Hall ,&nbsp;Christina Lam ,&nbsp;Lynne Wolfe ,&nbsp;Andrew Edmondson ,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101328","DOIUrl":"10.1016/j.gim.2024.101328","url":null,"abstract":"<div><div>Congenital disorders of glycosylation (CDG) are a large and continually expanding group of disorders that present with a variety of clinical findings and have been linked to over 170 genes. Individually, CDGs are rare; however, the true incidence may be underestimated because of the variability of the clinical findings, and the multiple testing strategies needed to diagnosis them across multiple pathways. Testing for CDGs has evolved over recent years with the availability of high-throughput molecular testing and improved gene discovery techniques. Biochemical testing to detect defects in glycosylated proteins or enzymatic deficiency still plays a critical role in the diagnosis of affected individuals, and both testing modalities are often required to finalize a diagnosis. Emerging therapeutic approaches targeting improvements in glycosylation require reliable and reproducible biochemical testing for therapeutic monitoring, dose adjustment, and avoidance of dose-related side effects. To maintain clinical sensitivity and specificity and to ensure reproducibility across laboratories performing complex biochemical testing, the American College of Medical Genetics and Genomics has developed the following technical standard.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101328"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405592","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}

{"title":"Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders","authors":"Elisa Cali ,&nbsp;Tania Quirin ,&nbsp;Clarissa Rocca ,&nbsp;Stephanie Efthymiou ,&nbsp;Antonella Riva ,&nbsp;Dana Marafi ,&nbsp;Maha S. Zaki ,&nbsp;Mohnish Suri ,&nbsp;Roberto Dominguez ,&nbsp;Hasnaa M. Elbendary ,&nbsp;Shahryar Alavi ,&nbsp;Mohamed S. Abdel-Hamid ,&nbsp;Heba Morsy ,&nbsp;Frederic Tran Mau-Them ,&nbsp;Mathilde Nizon ,&nbsp;Pavel Tesner ,&nbsp;Lukáš Ryba ,&nbsp;Faisal Zafar ,&nbsp;Nuzhat Rana ,&nbsp;Nebal W. Saadi ,&nbsp;Reza Maroofian","doi":"10.1016/j.gim.2024.101251","DOIUrl":"10.1016/j.gim.2024.101251","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aims to comprehensively delineate the phenotypic spectrum of <em>ACTL6B</em>-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.</div></div><div><h3>Methods</h3><div>We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of <em>ACTL6B</em> in ribosome biogenesis.</div></div><div><h3>Results</h3><div>Biallelic variants in <em>ACTL6B</em> are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing.</div></div><div><h3>Conclusion</h3><div>This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of <em>ACTL6B</em>-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of “ribosomopathies.”</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101251"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262256","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}

{"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}