Genetics in Medicine最新文献

{"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}

{"title":"Correspondence on “Weighty matters: Considering the ethics of genetic risk scores for obesity” by C. Houtz","authors":"John J. Connolly ,&nbsp;Molly Hess ,&nbsp;Priyanka Maripuri ,&nbsp;Shannon Terek ,&nbsp;Jasmine Purcell ,&nbsp;Margaret H. Harr ,&nbsp;Frank D. Mentch ,&nbsp;Joseph T. Glessner ,&nbsp;Rachana Shah ,&nbsp;Cindy A. Prows ,&nbsp;Dean J. Karavite ,&nbsp;Jeritt G. Thayer ,&nbsp;Robert W. Grundmeier ,&nbsp;Hakon Hakonarson ,&nbsp;eMERGE Network","doi":"10.1016/j.gim.2024.101324","DOIUrl":"10.1016/j.gim.2024.101324","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101324"},"PeriodicalIF":6.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618567","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":"Distinct rates of VUS reclassification are observed when subclassifying VUS by evidence level","authors":"Gwendolyn Bennett ,&nbsp;Izabela Karbassi ,&nbsp;Wenjie Chen ,&nbsp;Steven M. Harrison ,&nbsp;Matthew S. Lebo ,&nbsp;Linyan Meng ,&nbsp;Narasimhan Nagan ,&nbsp;Robert Rigobello ,&nbsp;Heidi L. Rehm","doi":"10.1016/j.gim.2025.101400","DOIUrl":"10.1016/j.gim.2025.101400","url":null,"abstract":"<div><h3>Purpose</h3><div>Genetic testing commonly yields a plethora of variants of uncertain significance (VUS) that can lead to ongoing uncertainty for patients and their caregivers. Although all VUS hold uncertainty, some VUS have more evidence in support of pathogenicity, whereas others have more evidence of a benign role. Sharing these nuances can help guide the investment in follow-up clinical and research investigations and may, at times, influence medical decision making despite appreciated uncertainty.</div></div><div><h3>Methods</h3><div>Four clinical laboratories have been subclassifying VUS to help prioritize investigation and guide reporting decisions. Each laboratory developed a distinct approach for how these subclasses are used in their laboratories and, in some cases, displayed on reports. We examined the composition of each laboratory’s VUS subclasses and the likelihood variants from each subclass were reclassified toward pathogenic or benign.</div></div><div><h3>Results</h3><div>We found that variants in the lowest subclass of VUS were never reclassified as likely pathogenic or pathogenic, whereas those in the highest subclass were much more likely to be reclassified as pathogenic or likely pathogenic.</div></div><div><h3>Conclusion</h3><div>Given that forthcoming professional guidance in variant classification will advise the use of VUS subclasses, the experience of our laboratories in using VUS subclasses can inform future practices.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101400"},"PeriodicalIF":6.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540994","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":"Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy","authors":"Jonathan De Winter ,&nbsp;Liedewei Van de Vondel ,&nbsp;Biljana Ermanoska ,&nbsp;Alice Monticelli ,&nbsp;Arnaud Isapof ,&nbsp;Enzo Cohen ,&nbsp;Tanya Stojkovic ,&nbsp;Peter Hackman ,&nbsp;Mridul Johari ,&nbsp;Johanna Palmio ,&nbsp;Megan A. Waldrop ,&nbsp;Alayne P. Meyer ,&nbsp;Stefan Nicolau ,&nbsp;Kevin M. Flanigan ,&nbsp;Ana Töpf ,&nbsp;Jordi Diaz-Manera ,&nbsp;Volker Straub ,&nbsp;Cheryl Longman ,&nbsp;Catherine A. McWilliam ,&nbsp;Rotem Orbach ,&nbsp;Jonathan Baets","doi":"10.1016/j.gim.2025.101399","DOIUrl":"10.1016/j.gim.2025.101399","url":null,"abstract":"<div><h3>Purpose</h3><div>Heterozygous pathogenic variants in <em>SPTAN1</em> cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of <em>SPTAN1</em> in genetically unsolved hereditary myopathies.</div></div><div><h3>Methods</h3><div>Through international collaboration we identified 14 families with distal weakness and heterozygous <em>SPTAN1</em> loss-of-function variants. Clinical data, electrophysiology, muscle computed tomography or magnetic resonance imaging, and muscle biopsy findings were collected and standardized. <em>SPTAN1</em> protein, messenger RNA expression analysis and copy DNA sequencing was performed on muscle tissue from 2 participants.</div></div><div><h3>Results</h3><div>Five families showed autosomal dominant mode of inheritance, whereas in 9 patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In 2 families, further segregation analysis was not possible. All affected participants presented with early childhood-onset distal weakness and foot abnormalities. Muscle magnetic resonance imaging or computed tomography in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense-mediated decay in muscle tissue derived from 2 patients.</div></div><div><h3>Conclusion</h3><div>We present evidence linking heterozygous <em>SPTAN1</em> loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101399"},"PeriodicalIF":6.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536972","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 meta-analysis of diagnostic yield and clinical utility of genome and exome sequencing in pediatric rare and undiagnosed genetic diseases","authors":"Rajshree Pandey ,&nbsp;Noemi Fluetsch Brennan ,&nbsp;Kalliopi Trachana ,&nbsp;Sarah Katsandres ,&nbsp;Olaf Bodamer ,&nbsp;John Belmont ,&nbsp;David L. Veenstra ,&nbsp;Siyang Peng","doi":"10.1016/j.gim.2025.101398","DOIUrl":"10.1016/j.gim.2025.101398","url":null,"abstract":"<div><h3>Purpose</h3><div>To systematically evaluate the diagnostic yield and clinical utility of genome sequencing (GS) and exome sequencing (ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases.</div></div><div><h3>Methods</h3><div>We conducted a meta-analysis of studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies using random-effects models.</div></div><div><h3>Results</h3><div>We identified 108 studies including 24,631 probands with diverse clinical indications. The pooled diagnostic yield among within-cohort studies (<em>N</em> = 13) for GWS was 34.2% (95% CI: 27.6-41.5; <em>I</em>^<em>2</em>: 86%) vs 18.1% (95% CI: 13.1-24.6; <em>I</em>^<em>2</em>: 89%) for non-GWS, with 2.4-times odds of diagnosis (95% CI: 1.40-4.04; <em>P</em> &lt; .05). The pooled diagnostic yield among within-cohort studies (<em>N</em> = 3) for GS was 30.6% (95% CI: 18.6-45.9; <em>I</em>^<em>2</em>: 79%) vs 23.2% (95% CI: 18.5-28.7; <em>I</em>^<em>2</em>: 58%) for ES, with 1.7-times the odds of diagnosis (95% CI: 0.94-2.92; <em>P</em> = .13). In first-line testing, the diagnostic yield tended to be higher for GS than for ES across clinical subgroups. The pooled clinical utility among patients with a positive diagnosis was 58.7% (95% CI: 47.3-69.2; <em>I</em>²: 81%) for GS and 54.5% (95% CI: 40.7-67.6; <em>I</em> ²: 87%) for ES.</div></div><div><h3>Conclusion</h3><div>GS appears to have a higher diagnostic yield than ES, with similar clinical utility per positive diagnosis.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101398"},"PeriodicalIF":6.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531260","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":"Recognizing the evolution of clinical syndrome spectrum progression in individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS).","authors":"Rebecca Ganetzky, Katelynn D Stanley, Laura E MacMullen, Ibrahim George-Sankoh, Jing Wang, Amy Goldstein, Rui Xiao, Marni J Falk","doi":"10.1016/j.gim.2025.101386","DOIUrl":"10.1016/j.gim.2025.101386","url":null,"abstract":"<p><strong>Purpose: </strong>Single large-scale mtDNA deletions (SLSMD) result in single large-scale deletion syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least 3 distinct clinical phenotypes: Pearson syndrome (PS), Kearns-Sayre syndrome (KSS), and chronic progressive ophthalmoplegia.</p><p><strong>Methods: </strong>A facilitated review of electronic medical records, manual charts, and Research Electronic Data Capture research databases was performed to complete a retrospective natural history study of 30 participants with SLSMDS in a single health system between 2002 and 2020. The evaluated characteristics included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient-reported outcome measures of fatigue, quality of life, and overall function.</p><p><strong>Results: </strong>Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 (HGNC:7641) occurs in 96% of participants with SLSMDS regardless of the clinical phenotype, which tends to evolve over time. Higher blood heteroplasmy correlated with an earlier age of onset. Growth differentiation factor 15 levels were elevated in all participants with SLSMDS. A history of PS was associated with poor survival prognosis. Furthermore, increased fatigue and decreased quality of life have been reported in patients with SLSMD with advanced age.</p><p><strong>Conclusion: </strong>A retrospective natural history study of patients with SLSMDS demonstrated the evolution of classically considered PS, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia clinical presentations in affected individuals, which may inform future clinical trial developments.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101386"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476431","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":"How do parents decide on genetic testing in pediatrics? A systematic review","authors":"Elena Sophia Doll ,&nbsp;Seraina Petra Lerch ,&nbsp;Katja Maria Schmalenberger ,&nbsp;Karla Alex ,&nbsp;Stefan Kölker ,&nbsp;Heiko Brennenstuhl ,&nbsp;Stacey Pereira ,&nbsp;Hadley Smith ,&nbsp;Eva Caroline Winkler ,&nbsp;Julia Mahal ,&nbsp;Beate Ditzen","doi":"10.1016/j.gim.2025.101390","DOIUrl":"10.1016/j.gim.2025.101390","url":null,"abstract":"<div><h3>Purpose</h3><div>This systematic review aims to identify the factors that influence parents’ decisions regarding pediatric diagnostic genetic testing (DT) and predictive genetic testing (PT). These factors are integrated into a conceptual decision-making model. Implications for genetic counseling, research, and ethics were derived.</div></div><div><h3>Methods</h3><div>PubMed, PsychInfo, WebofScience, and related references were searched for original publications between 2000 and 2023. The extracted factors were categorized using existing models.</div></div><div><h3>Results</h3><div>Of the 5843 publications, 56 met the inclusion criteria. The included studies differentiated between DT, traditional PT, and expanded PT and described factors affecting parental decisions to have the child genetically tested and to be informed about additional findings. Factors included (1) benefits/hopes, (2) worries/concerns, (3) values and beliefs, (4) individual circumstances, and (5) emotional states.</div></div><div><h3>Conclusion</h3><div>Our work extends the existing empirical decision model of family decisions about genome sequencing to genetic testing in pediatrics in general, adding the categories of individual circumstances and emotional states. These factors can be further integrated into the Health Belief Model; the importance of emotional states is reflected in dual-process theories, such as the Fuzzy Trace Theory. Research is required on emotional states, differences between DT and PT, parents’ decisions regarding result disclosure, and dyadic variables as decision-making predictors.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101390"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482968","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":"Parents’ perceptions of the utility of genetic testing in the NICU","authors":"Katharine Press Callahan ,&nbsp;Rebecca Mueller ,&nbsp;Steven Joffe ,&nbsp;Cara Skraban ,&nbsp;Nancy B. Spinner ,&nbsp;Karen Crew ,&nbsp;Justin Clapp ,&nbsp;David Munson ,&nbsp;Chris Feudtner","doi":"10.1016/j.gim.2025.101393","DOIUrl":"10.1016/j.gim.2025.101393","url":null,"abstract":"<div><h3>Purpose</h3><div>Although several studies have evaluated the perspectives of parents in the neonatal intensive care unit on the utility of genetic testing in a research context and concluded with a positive appraisal, some data point to more varied perceptions.</div></div><div><h3>Methods</h3><div>Semistructured interviews were conducted to elicit parental beliefs about the ways in which clinical (nonresearch) genetic testing could be both helpful and harmful.</div></div><div><h3>Results</h3><div>We interviewed 43 parents of 36 neonates who were recommended and either accepted or declined to participate in clinical genetic testing. Parents described 5 types of problems they believed genetic information may address, what we term problem-solving contexts: treatment, coping, parenting, prognostic, and existential contexts. Most parents consider multiple problem-solving contexts when assessing benefits, which frequently results in ambivalence.</div></div><div><h3>Conclusion</h3><div>Parents in the neonatal intensive care unit appear to be more ambivalent about the utility of genetic information than has been reflected in most recent studies. This discrepancy is likely related to our sample population, clinical rather than research methodology, which encouraged parents to discuss contexts beyond the medical field. Our findings suggest that informed pretest consent discussions and posttest counseling should encourage parents to discuss multiple problem-solving contexts. Researchers should also find ways to incorporate multiple contexts and diverse perspectives into their utility measures.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101393"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482969","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":"ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time","authors":"Kezang C. Tshering ,&nbsp;Marina T. DiStefano ,&nbsp;Andrea M. Oza ,&nbsp;Pamela Ajuyah ,&nbsp;Ryan Webb ,&nbsp;Enyonam Edoh ,&nbsp;Ellie Broeren ,&nbsp;Julie Ratliff ,&nbsp;Vanessa Gitau ,&nbsp;Kelley Paris ,&nbsp;Amal Aburyyan ,&nbsp;John Alexander ,&nbsp;Victoria Albano ,&nbsp;Donglin Bai ,&nbsp;Kevin T.A. Booth ,&nbsp;Paula I. Buonfiglio ,&nbsp;Cherine Charfeddine ,&nbsp;Viviana Dalamón ,&nbsp;Ignacio del Castillo ,&nbsp;Miguel Angel Moreno-Pelayo ,&nbsp;Zubair Ahmed","doi":"10.1016/j.gim.2025.101392","DOIUrl":"10.1016/j.gim.2025.101392","url":null,"abstract":"<div><h3>Purpose</h3><div>The Clinical Genome Resource (ClinGen) Hearing Loss Gene Curation Expert Panel was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen’s semiquantitative framework. ClinGen mandates the timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong every 2 to 3 years.</div></div><div><h3>Methods</h3><div>Thirty-five GDRs met the criteria for recuration within 2 years of original curation. Previous evidence was reevaluated using the latest curation guidelines, and a comprehensive literature review was performed to obtain new evidence. Recurations were approved by the Gene Curation Expert Panel and published on the ClinGen website (<span><span>www.clinicalgenome.org</span><svg><path></path></svg></span>).</div></div><div><h3>Results</h3><div>Eight of 35 GDRs (22%) changed their classification. Two Moderate and 5 Strong GDRs were upgraded to Definitive because of new case evidence. One Strong was subsumed under another Definitive GDR after evaluation of the lumping/splitting of disease entities. Twenty-seven of 35 patients remained unchanged, with little to no new evidence reported.</div></div><div><h3>Conclusion</h3><div>Genes classified as Moderate and Strong were likely to build evidence and change their classification over time, whereas Limited were unlikely to gain evidence. These findings highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most recent evidence into their efforts.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101392"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482967","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":"DICER1 in pediatric and adult cancer predisposition populations: Prevalence, phenotypes, and mosaicism","authors":"Lluis Salvador ,&nbsp;Jesús del Valle ,&nbsp;Eduard Dorca ,&nbsp;Anne-Sophie Chong ,&nbsp;Anne-Laure Chong ,&nbsp;José Camacho Valenzuela ,&nbsp;Elisabet Munté ,&nbsp;Cristina Rioja ,&nbsp;Laura Martí-Sánchez ,&nbsp;Mónica Salinas ,&nbsp;Esther Darder ,&nbsp;Marc R. Fabian ,&nbsp;Joan Brunet ,&nbsp;Hector Salvador ,&nbsp;Conxi Lázaro ,&nbsp;Barbara Rivera","doi":"10.1016/j.gim.2025.101385","DOIUrl":"10.1016/j.gim.2025.101385","url":null,"abstract":"<div><h3>Purpose</h3><div>DICER1 tumor predisposition syndrome (DTPS) is a hereditary condition affecting children and young adults. Identification of <em>DICER1</em> carriers is key for prevention and actionability in families. However, DTPS diagnosis is hindered by its incomplete penetrance and broad phenotypic spectrum.</div></div><div><h3>Methods</h3><div>We performed an analysis of <em>DICER1</em> sequencing data from 92 children and 6108 adults with suspected cancer predisposition syndrome. Clinical and <em>DICER1</em> somatic data from selected carriers and public data sets were studied.</div></div><div><h3>Results</h3><div>The prevalence of germline <em>DICER1</em> pathogenic variants was 1:30 in children and 1:3054 in adults. No adult referral phenotype was a known DTPS-associated tumor, although 3 of 5 carriers developed thyroid alterations. We provide functional evidence supporting the pathogenicity of a novel in-frame deletion. A 56-year-old woman with ovarian carcinoma and toxic diffuse thyroid hyperplasia was found to have a postzygotic hotspot missense variant.</div></div><div><h3>Conclusion</h3><div>The prevalence of <em>DICER1</em> pathogenic variants in cancer predisposition populations was 5 to 6 times that reported in the general population. Pediatric-onset DTPS is well characterized, whereas adult carriers mainly present with thyroid abnormalities in the absence of DICER1-related family history, thus requiring accurate criteria for its identification when in constellation with other tumor types. Postzygotic hotspot missense variants may exist without the expected severe phenotype.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101385"},"PeriodicalIF":6.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457534","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}