Genetics in Medicine最新文献_第6页

Points to consider for the reporting of variants of uncertain significance in germline genetic and genomic testing: A statement of the American College of Medical Genetics and Genomics (ACMG) 在生殖系遗传和基因组检测中报告不确定意义的变异时应考虑的要点：美国医学遗传学和基因组学学院（ACMG）的声明。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-07-01 Epub Date: 2026-06-12 DOI: 10.1016/j.gim.2026.102583

Chloe Mighton, Aya Abu-El-Haija, Vimla Aggarwal, Yassmine M.N. Akkari, Caroline Astbury, D. Hunter Best, Laura K. Conlin, Steven M. Harrison, Nan Jiang, Paul Kruszka, Dianalee McKnight, Tiffany T. Nguyen Dolphyn, Farid Barquet Ramos, Christie P. Thomas, Lora J.H. Bean, Heidi L. Rehm, Laboratory Quality Assurance Committee

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Genetic findings and health care utilization among individuals undergoing population genomic screening for actionable hereditary disorders 遗传发现和医疗保健利用的个人进行人群基因组筛查的可操作的遗传性疾病。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-07-01 Epub Date: 2026-05-19 DOI: 10.1016/j.gim.2026.102605

Tali Ekstein, Sienna Aguilar, Emily M. Russell, Rachel E. Ellsworth, Kurt D. Christensen, Peter Hulick, Robert Green, Robert Nussbaum, Swaroop Aradhya, John Garcia

{"title":"Genetic findings and health care utilization among individuals undergoing population genomic screening for actionable hereditary disorders","authors":"Tali Ekstein, Sienna Aguilar, Emily M. Russell, Rachel E. Ellsworth, Kurt D. Christensen, Peter Hulick, Robert Green, Robert Nussbaum, Swaroop Aradhya, John Garcia","doi":"10.1016/j.gim.2026.102605","DOIUrl":"10.1016/j.gim.2026.102605","url":null,"abstract":"<div><h3>Purpose</h3><div>Genomic screening (GS) can identify the risk of medically actionable, monogenic conditions in individuals who would otherwise not be considered for genetic testing. The yield of pathogenic variants and associated health care utilization among at-risk individuals have not been well-studied in real-world settings.</div></div><div><h3>Methods</h3><div>Physicians ordered GS panels for up to 167 genes. Calculations included the positive yield overall and for 81 genes on the American College of Medical Genetics and Genomics’ secondary findings list. Health care utilization and costs were analyzed using insurance claims from 12 months before and after the genetic test results.</div></div><div><h3>Results</h3><div>Among 50,063 individuals, 8.6% had pathogenic/likely pathogenic variants conferring monogenic risk. Relevant health care utilization was higher in individuals with positive results than in those with non-positive results. There was a small but significant increase in median cost of all-cause health care utilization post-test compared with pre-test in participants with positive ($340 vs $215, <em>P</em> = .02) but not negative results ($308 vs $252, <em>P</em> = .12).</div></div><div><h3>Conclusion</h3><div>These findings suggest that GS in real-world settings can identify at-risk individuals and prompt intervention without significantly increasing health care costs or utilization.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 7","pages":"Article 102605"},"PeriodicalIF":6.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147972008","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}

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Reproductive Carrier Screening Detects Early Actionable Metabolic Conditions. 生殖载体筛选检测早期可操作的代谢条件。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-06-16 DOI: 10.1016/j.gim.2026.102634

Christian M Parobek, Roni Zemet, Vivienne Souter, Elizabeth Repass, Eugenia Martinez Jaime, Ashley Cantu-Weinstein, Yang Wang, Jeffrey Dungan, V Reid Sutton

{"title":"Reproductive Carrier Screening Detects Early Actionable Metabolic Conditions.","authors":"Christian M Parobek, Roni Zemet, Vivienne Souter, Elizabeth Repass, Eugenia Martinez Jaime, Ashley Cantu-Weinstein, Yang Wang, Jeffrey Dungan, V Reid Sutton","doi":"10.1016/j.gim.2026.102634","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102634","url":null,"abstract":"<p><strong>Purpose: </strong>Early actionable metabolic conditions (EAMCs) are disorders that are often severe but have early interventions that can improve clinical outcomes. EAMCs are not universally included on newborn screening panels. We studied the clinical utility of detecting EAMC gene variants prenatally using reproductive carrier screening (RCS).</p><p><strong>Methods: </strong>We identified EAMCs from the 113 ACMG-recommended carrier panel and a 275-gene carrier panel. The carrier status for these EAMCs was determined in a cohort of women who underwent RCS between 2022 and 2024. Observed carrier frequencies were used to calculate theoretical affected pregnancy rates.</p><p><strong>Results: </strong>110 EAMCs were identified. Among 54,119 individuals, the carrier frequency for any EAMC was 1 in 6, using the 113-gene panel, and 1 in 4, using the 275-gene panel. Assuming random pairing, the theoretical affected pregnancy rates were 0.07% with the 113-gene panel and 0.08% with the 275-gene panel. The most prevalent EAMCs in this cohort were phenylketonuria (MIM:261600, 1 in 41), congenital adrenal hyperplasia (MIM:201910, 1 in 57), Wilson disease (MIM:201910, 1 in 63), Smith-Lemli-Opitz syndrome (MIM:270400, 1 in 75), and medium-chain acyl-CoA dehydrogenase deficiency (MIM:201450, 1 in 80).</p><p><strong>Conclusion: </strong>RCS facilitates detection and early intervention, which may reduce associated morbidity for certain metabolic disorders.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102634"},"PeriodicalIF":6.2,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258049","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}

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Response to Wojcik and Fraiman 对沃西克和弗雷曼的回应。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-06-01 Epub Date: 2026-06-17 DOI: 10.1016/j.gim.2026.102576

Steven Pastor, Oanh Tran, Ryan Lapointe, Arnold Z. Olali, Douglas C. Wallace, Bernice Morrow, Elaine H. Zackai, Donna M. McDonald-McGinn, Beverly S. Emanuel

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Correspondence on “Optical mapping in Black genomes: Distinct LCR22 structures and 22q11.2 deletion syndrome mechanisms” by Pastor et al Pastor等人对“黑人基因组中的光学定位：不同的LCR22结构和22q11.2缺失综合征机制”的对应。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-06-01 Epub Date: 2026-06-17 DOI: 10.1016/j.gim.2026.102575

Yarden S. Fraiman, Monica H. Wojcik

引用次数: 0

Calibration and evaluation of machine-learning algorithms for missense variant classification under ACMG/ClinGen recommendations. ACMG/ClinGen建议下错义变体分类机器学习算法的校准和评估。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-05-20 DOI: 10.1016/j.gim.2026.102606

Xinming Zhuo, Xin Bi, Vimla Aggarwal, Jun Liao

{"title":"Calibration and evaluation of machine-learning algorithms for missense variant classification under ACMG/ClinGen recommendations.","authors":"Xinming Zhuo, Xin Bi, Vimla Aggarwal, Jun Liao","doi":"10.1016/j.gim.2026.102606","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102606","url":null,"abstract":"<p><strong>Purpose: </strong>Missense variants represent a large proportion of variants of uncertain significance (VUS) in clinical genetics. The ClinGen framework now enables quantitative use of in silico predictors for variant classification (PP3/BP4), but newly developed machine-learning-based tools such as AlphaMissense (AM) and PrimateAI-3D (PAI3D) have not been evaluated in this context using real-world clinical data.</p><p><strong>Methods: </strong>We calibrated AM and PAI3D using ClinGen's quantitative framework and assessed their performance alongside REVEL, a widely used meta-predictor, across three datasets: ClinVar_2023, ClinGen, and Columbia Diagnostic Exome Sequencing (CDEX). Predictive performance was evaluated using area under the curve (AUC), F1 scores, and classification impact on VUS.</p><p><strong>Results: </strong>REVEL demonstrated the highest overall performance, particularly for autosomal recessive variants and autosomal dominant variants tolerant to loss-of-function. AM outperformed other tools for autosomal dominant variants in haploinsufficiency genes. Applying updated PP3/BP4 criteria to ClinGen VUS resulted in over 10% being upgraded to likely pathogenic and less than 3% downgraded to likely benign, with REVEL yielding the most LP upgrades and AM the most LB downgrades.</p><p><strong>Conclusion: </strong>Our findings highlight the complementary strengths of AM, PAI3D, and REVEL under the ClinGen framework, supporting more accurate and mechanism-aware missense variant classification in clinical settings.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102606"},"PeriodicalIF":6.2,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971996","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}

引用次数: 0

Evidence-based multidisciplinary model of care for newborn screening in spinal muscular atrophy 新生儿脊髓性肌萎缩症筛查的循证多学科护理模式。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-05-01 Epub Date: 2026-05-07 DOI: 10.1016/j.gim.2026.102560

Didu S. Kariyawasam , C.E. Meagher , A. Kay , A. Cairns , C. Siu , C. Wedlake, C. Lau , C. Miller , D. Clark , D. Webster , E. Mas , E.M. Yiu , F. Tolich, F. Moore , G. Crisp , G. O’Grady , H. Sampaio , J. Pitt , J. Cini , K. Bhattacharya , M.A. Farrar

{"title":"Evidence-based multidisciplinary model of care for newborn screening in spinal muscular atrophy","authors":"Didu S. Kariyawasam , C.E. Meagher , A. Kay , A. Cairns , C. Siu , C. Wedlake, C. Lau , C. Miller , D. Clark , D. Webster , E. Mas , E.M. Yiu , F. Tolich, F. Moore , G. Crisp , G. O’Grady , H. Sampaio , J. Pitt , J. Cini , K. Bhattacharya , M.A. Farrar","doi":"10.1016/j.gim.2026.102560","DOIUrl":"10.1016/j.gim.2026.102560","url":null,"abstract":"<div><h3>Purpose</h3><div>Newborn screening for spinal muscular atrophy provides expedient access to diagnosis and treatment to transform health outcomes. However, because of a lack of high-quality practice standards and inequitable care and support access, health outcomes for affected children vary substantially. The study’s purpose was to develop evidence and consensus-based recommendations to optimize and standardize clinical pathways.</div></div><div><h3>Methods</h3><div>A total of 35 experts prepared systematic reviews and formulated recommendations using a modified Delphi process. Recommendations were developed for screening, diagnostic, and clinical domains, alongside guidelines to inform the content and quality of information provision and genetic counseling for families.</div></div><div><h3>Results</h3><div>The study generated 25 best practice recommendations. These encompassed pathways to expedite time to diagnosis and treatment through collaboration and coordination between health care services, standardization of screening and diagnostic methodologies, and equitable provision and timely access to specialist care and support.</div></div><div><h3>Conclusion</h3><div>The study informs best practice within a new diagnostic and therapeutic era for spinal muscular atrophy by providing an evidence-based translational framework to improve the health and well-being of affected children. As implementation of these public health programs accelerate globally, this study provides health care professionals and policy makers with a template to develop feasible and equitable newborn screening programs for spinal muscular atrophy.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 5","pages":"Article 102560"},"PeriodicalIF":6.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836472","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}

引用次数: 0

Germline ATRIP variants and the risk of ovarian cancer 种系ATRIP变异与卵巢癌的风险。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-05-01 Epub Date: 2026-05-12 DOI: 10.1016/j.gim.2026.102547

Neda Zamani , Dominika Wokołorczyk , Wojciech Kluźniak , Alicja Ogrodniczak , Anna Jakubowska , Mehar Chahal , Klaudia Stempa , Katarzyna Gliniewicz , Tomasz Huzarski , Helena Rudnicka , Marek Szwiec , Malgorzata Stawicka , Ewa Kaznowska , Tomasz Kluz , Paweł Domagała , Tadeusz Dębniak , John McLaughlin , Jan Lubiński , Jacek Gronwald , Steven A. Narod , Mohammad R. Akbari

{"title":"Germline ATRIP variants and the risk of ovarian cancer","authors":"Neda Zamani , Dominika Wokołorczyk , Wojciech Kluźniak , Alicja Ogrodniczak , Anna Jakubowska , Mehar Chahal , Klaudia Stempa , Katarzyna Gliniewicz , Tomasz Huzarski , Helena Rudnicka , Marek Szwiec , Malgorzata Stawicka , Ewa Kaznowska , Tomasz Kluz , Paweł Domagała , Tadeusz Dębniak , John McLaughlin , Jan Lubiński , Jacek Gronwald , Steven A. Narod , Mohammad R. Akbari","doi":"10.1016/j.gim.2026.102547","DOIUrl":"10.1016/j.gim.2026.102547","url":null,"abstract":"<div><h3>Purpose</h3><div>We have previously reported that inherited variants in <em>ATRIP</em> confer a 3-fold risk of developing breast cancer. Here, we investigated potential association between this novel breast cancer susceptibility gene and the risk of ovarian cancer.</div></div><div><h3>Methods</h3><div>We genotyped the <em>ATRIP</em> c.1152_1155del p.(Gly385Ter) Polish founder variant on germline DNA from 3404 Polish women with ovarian cancer and 9285 healthy controls. Additionally, we sequenced all coding exons of <em>ATRIP</em> among 1322 unselected ovarian cancer patients and 930 cancer-free women from Ontario, Canada.</div></div><div><h3>Results</h3><div>The heterozygous <em>ATRIP</em> c.1152_1155del p.(Gly385Ter) variant was identified in 8 of 3404 ovarian cancer cases and 11 of 9285 controls in the Polish population (OR = 1.98, 95% CI = 0.79-4.94, <em>P</em> = .19). In the Ontario cohort, 4 ovarian cancer cases harbored <em>ATRIP</em> loss-of-function (LoF) variants, versus none observed among controls (OR = 5.6, <em>P</em> = .14). In a combined analysis of both cohorts, adjusted for age, self-reported ethnicity, and study, <em>ATRIP</em> LoF variants were significantly associated with ovarian cancer risk (OR = 2.51, 95% CI = 1.108-5.699, <em>P</em> = .037).</div></div><div><h3>Conclusion</h3><div><em>ATRIP</em> plays a critical role in DNA damage response and genomic stability. Our findings support its candidacy as a novel ovarian cancer susceptibility gene.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 5","pages":"Article 102547"},"PeriodicalIF":6.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873850","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}

引用次数: 0

Incorporation of clinical and molecular variant properties improves the performance of in silico pathogenicity prediction tools 临床和分子变异特性的结合提高了硅致病性预测工具的性能。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-05-01 Epub Date: 2026-03-26 DOI: 10.1016/j.gim.2026.102557

Ofer Isakov , Reut Ashwal-Fluss , Dina Marek-Yagel , Shamil Sunyaev , Shay Ben-Shachar

{"title":"Incorporation of clinical and molecular variant properties improves the performance of in silico pathogenicity prediction tools","authors":"Ofer Isakov , Reut Ashwal-Fluss , Dina Marek-Yagel , Shamil Sunyaev , Shay Ben-Shachar","doi":"10.1016/j.gim.2026.102557","DOIUrl":"10.1016/j.gim.2026.102557","url":null,"abstract":"<div><h3>Purpose</h3><div>In silico pathogenicity prediction tools performance can vary depending on molecular and clinical contexts. This study aims to assess the performance of commonly used tools under different conditions. Additionally, the study aims to recalibrate score thresholds to better reflect evidence of pathogenicity.</div></div><div><h3>Methods</h3><div>ClinVar variants were stratified by allele frequency, conservation, mode of inheritance, and disease category. For each subset, Bayesian methods were used to recalibrate thresholds corresponding to the levels of evidence defined by the American College of Medical Genetics.</div></div><div><h3>Results</h3><div>Tools exhibited reduced accuracy for variants with higher allele frequencies and for variants located in regions with high conservation. Variants affecting autosomal recessive and X-linked genes were more accurately classified compared with those affecting autosomal dominant genes. Recalibrated thresholds consistently showed higher odds of correctly estimating pathogenicity (OR=3.78 [1.74, 8.55]; <em>P</em> < .001) and produced significantly higher scores for known pathogenic variants and lower scores for benign/likely benign. This improved discriminatory performance was particularly notable in variants found in low-conservation regions and autosomal recessive genes.</div></div><div><h3>Conclusion</h3><div>Pathogenicity prediction tools should be evaluated using various variant subsets during development. Score threshold recalibration extends the range of evidence and improves overall pathogenicity probability estimation and classification.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 5","pages":"Article 102557"},"PeriodicalIF":6.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147573672","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}

引用次数: 0

Correspondence on “Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome” by Valenzuela et al Valenzuela等人对“11例RNU4-2致病性变异个体的深度表型分析揭示了一种临床可识别的综合征”的对应。

IF 6.2 1区医学

Genetics in Medicine Pub Date : 2026-04-01 Epub Date: 2026-01-19 DOI: 10.1016/j.gim.2026.101686

Zarnab Saleem , Jawairya Muhammad Hussain , Qurat-ul-Ain Siddiqui , Sarah Zuberi

引用次数: 0