Genetics in Medicine最新文献

{"title":"Clinical signatures of genetic epilepsies precede diagnosis in electronic medical records of 32,000 individuals","authors":"Peter D. Galer ,&nbsp;Shridhar Parthasarathy ,&nbsp;Julie Xian ,&nbsp;Jillian L. McKee ,&nbsp;Sarah M. Ruggiero ,&nbsp;Shiva Ganesan ,&nbsp;Michael C. Kaufman ,&nbsp;Stacey R. Cohen ,&nbsp;Scott Haag ,&nbsp;Chen Chen ,&nbsp;William K.S. Ojemann ,&nbsp;Dan Kim ,&nbsp;Olivia Wilmarth ,&nbsp;Priya Vaidiswaran ,&nbsp;Casey Sederman ,&nbsp;Colin A. Ellis ,&nbsp;Alexander K. Gonzalez ,&nbsp;Christian M. Boßelmann ,&nbsp;Dennis Lal ,&nbsp;Rob Sederman ,&nbsp;Ingo Helbig","doi":"10.1016/j.gim.2024.101211","DOIUrl":"10.1016/j.gim.2024.101211","url":null,"abstract":"<div><h3>Purpose</h3><p>An early genetic diagnosis can guide the time-sensitive treatment of individuals with genetic epilepsies. However, most genetic diagnoses occur long after disease onset. We aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy through large-scale analysis of full-text electronic medical records.</p></div><div><h3>Methods</h3><p>We extracted 89 million time-stamped standardized clinical annotations using Natural Language Processing from 4,572,783 clinical notes from 32,112 individuals with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies. We applied these features to train random forest models to predict <em>SCN1A</em>-related disorders and any genetic diagnosis.</p></div><div><h3>Results</h3><p>We identified 47,774 age-dependent associations of clinical features with genetic etiologies a median of 3.6 years before molecular diagnosis. Across all 710 genetic etiologies identified in our cohort, neurodevelopmental differences between 6 to 9 months increased the likelihood of a later molecular diagnosis 5-fold (<em>P</em> &lt; .0001, 95% CI = 3.55-7.42). A later diagnosis of <em>SCN1A</em>-related disorders (area under the curve [AUC] = 0.91) or an overall positive genetic diagnosis (AUC = 0.82) could be reliably predicted using random forest models.</p></div><div><h3>Conclusion</h3><p>Clinical features predictive of genetic epilepsies precede molecular diagnoses by up to several years in conditions with known precision treatments. An earlier diagnosis facilitated by automated electronic medical records analysis has the potential for earlier targeted therapeutic strategies in the genetic epilepsies.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101211"},"PeriodicalIF":6.6,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619731","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 truth should not be hidden”: Experiences and recommendations of individuals making NPE discoveries through genetic genealogy databases","authors":"Olivia Schuman ,&nbsp;Caroline Beit ,&nbsp;Jill Oliver Robinson ,&nbsp;Whitney Bash Brooks ,&nbsp;Amy L. McGuire ,&nbsp;Christi Guerrini","doi":"10.1016/j.gim.2024.101210","DOIUrl":"10.1016/j.gim.2024.101210","url":null,"abstract":"<div><h3>Purpose</h3><p>Fueled by direct-to-consumer (DTC) genetic testing and genetic-relative finder services, some participants in genetic genealogy databases are making “not parent expected” (NPE) discoveries. To better understand experiences of this phenomenon, we surveyed a large cohort of users of genetic relative finder (GRF) services concerning their experiences after an NPE discovery.</p></div><div><h3>Methods</h3><p>Using thematic analysis, we analyzed responses from a cohort of GRF users (<em>n</em> = 646) to open-ended survey items to understand these experiences and their recommendations for DTC genetic testing companies and other GRF users.</p></div><div><h3>Results</h3><p>We found that individuals had both positive and negative emotional experiences related to the NPE discovery. Positive aspects included deeper self-understanding, connecting with new family members, and uncovering answers to questions. Negative aspects included rejection by new genetic relatives, inability to seek answers from relatives who had already died, and impairment of family relationships, especially with mothers. For many participants, the challenges after the discovery nevertheless felt worthwhile because the truth was uncovered. Perhaps notably, some participants suggested enhanced warnings prediscovery and improved support after discovery from companies who provide DTC genetic testing services.</p></div><div><h3>Conclusion</h3><p>GRF services are powerful tools for family research and genealogy. Despite some possible positive and worthwhile experiences arising from making an NPE discovery, GRF users risk dealing with this potentially life-altering experience without adequate support. Participants in this study recommended an increase in resources from DTC genetic testing companies that could help users anticipate and navigate an NPE discovery.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 10","pages":"Article 101210"},"PeriodicalIF":6.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603511","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 Undiagnosed Diseases Network: Characteristics of solvable applicants and diagnostic suggestions for nonaccepted ones","authors":"","doi":"10.1016/j.gim.2024.101203","DOIUrl":"10.1016/j.gim.2024.101203","url":null,"abstract":"<div><h3>Purpose</h3><p>Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, such as by the Undiagnosed Diseases Network (UDN)?</p></div><div><h3>Methods</h3><p>The UDN is a national research resource to solve medical mysteries through team science. Applicants provide informed consent to access to their medical records. After review, expert panels assess if applicants meet inclusion and exclusion criteria to select participants. When not accepting applicants, UDN experts may offer suggestions for diagnostic efforts. Using minimal information from initial applications, we compare features in applicants who are not accepted with those who are accepted and either solved or still not solved by the UDN. The diagnostic suggestions offered to nonaccepted applicants and their clinicians were tallied.</p></div><div><h3>Results</h3><p>Nonaccepted applicants were more often female, older at first symptoms and application, and longer in review compared with accepted applicants. The accepted and successfully diagnosed applicants were younger, shorter in review time, more often non-White, of Hispanic ethnicity, and presenting with nervous system features. Half of nonaccepted applicants were given suggestions for further local diagnostic evaluation. A few seemed to have 2 major diagnoses or a provocative environmental exposure history.</p></div><div><h3>Conclusion</h3><p>Comprehensive UDN record review generates possibly helpful advice.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 10","pages":"Article 101203"},"PeriodicalIF":6.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534209","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 “Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants” by Wermers et al","authors":"Mark J. Kiel,&nbsp;Amina Kozaric","doi":"10.1016/j.gim.2024.101161","DOIUrl":"10.1016/j.gim.2024.101161","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 7","pages":"Article 101161"},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897174","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 Kiel and Kozaric","authors":"Zara Wermers,&nbsp;Seeley Yoo,&nbsp;Bailey Radenbaugh,&nbsp;Amber Douglass,&nbsp;Leslie G. Biesecker,&nbsp;Jennifer J. Johnston","doi":"10.1016/j.gim.2024.101162","DOIUrl":"10.1016/j.gim.2024.101162","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 7","pages":"Article 101162"},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897176","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":"Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants","authors":"Zara Wermers,&nbsp;Seeley Yoo,&nbsp;Bailey Radenbaugh,&nbsp;Amber Douglass,&nbsp;Leslie G. Biesecker,&nbsp;Jennifer J. Johnston","doi":"10.1016/j.gim.2024.101157","DOIUrl":"10.1016/j.gim.2024.101157","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 7","pages":"Article 101157"},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024000911/pdfft?md5=5a0c665d30aa2128da5172370fb6772a&pid=1-s2.0-S1098360024000911-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946821","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":"Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors","authors":"Brent Mabey ,&nbsp;Elisha Hughes ,&nbsp;Matthew Kucera ,&nbsp;Timothy Simmons ,&nbsp;Brooke Hullinger ,&nbsp;Holly J. Pederson ,&nbsp;Lamis Yehia ,&nbsp;Charis Eng ,&nbsp;Judy Garber ,&nbsp;Monique Gary ,&nbsp;Ora Gordon ,&nbsp;Jennifer R. Klemp ,&nbsp;Semanti Mukherjee ,&nbsp;Joseph Vijai ,&nbsp;Kenneth Offit ,&nbsp;Olufunmilayo I. Olopade ,&nbsp;Sandhya Pruthi ,&nbsp;Allison Kurian ,&nbsp;Mark E. Robson ,&nbsp;Pat W. Whitworth ,&nbsp;Alexander Gutin","doi":"10.1016/j.gim.2024.101128","DOIUrl":"10.1016/j.gim.2024.101128","url":null,"abstract":"<div><h3>Purpose</h3><p>We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort.</p></div><div><h3>Methods</h3><p>This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs.</p></div><div><h3>Results</h3><p>Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC.</p></div><div><h3>Conclusion</h3><p>CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 7","pages":"Article 101128"},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024000613/pdfft?md5=0062e60be32ca9cd24042faba911d08b&pid=1-s2.0-S1098360024000613-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199716","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":"Laboratory testing for preconception/prenatal carrier screening: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Saurav Guha ,&nbsp;Honey V. Reddi ,&nbsp;Mahmoud Aarabi ,&nbsp;Marina DiStefano ,&nbsp;Erin Wakeling ,&nbsp;Jeffrey S. Dungan ,&nbsp;Anthony R. Gregg ,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101137","DOIUrl":"10.1016/j.gim.2024.101137","url":null,"abstract":"<div><p>Carrier screening has historically assessed a relatively small number of autosomal recessive and X-linked conditions selected based on frequency in a specific subpopulation and association with severe morbidity or mortality. Advances in genomic technologies enable simultaneous screening of individuals for several conditions. The American College of Medical Genetics and Genomics recently published a clinical practice resource that presents a framework when offering screening for autosomal recessive and X-linked conditions during pregnancy and preconception and recommends a tier-based approach when considering the number of conditions to screen for and their frequency within the US population in general. This laboratory technical standard aims to complement the practice resource and to put forth considerations for clinical laboratories and clinicians who offer preconception/prenatal carrier screening.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 7","pages":"Article 101137"},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024000704/pdfft?md5=e2ddd184677a26ba495702091fc3037f&pid=1-s2.0-S1098360024000704-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174306","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":"Consideration of disease penetrance in the selection of secondary findings gene-disease pairs: A policy statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Adam S. Gordon ,&nbsp;Kristy Lee ,&nbsp;Noura S. Abul-Husn ,&nbsp;Laura M. Amendola ,&nbsp;Kyle Brothers ,&nbsp;Wendy K. Chung ,&nbsp;Michael H. Gollob ,&nbsp;Steven M. Harrison ,&nbsp;Ray E. Hershberger ,&nbsp;C. Sue Richards ,&nbsp;Douglas R. Stewart ,&nbsp;Christa Lese Martin ,&nbsp;David T. Miller ,&nbsp;ACMG Secondary Findings Working Group","doi":"10.1016/j.gim.2024.101142","DOIUrl":"10.1016/j.gim.2024.101142","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 7","pages":"Article 101142"},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024000753/pdfft?md5=40a8e32f5ef645a3ec87b5e053526507&pid=1-s2.0-S1098360024000753-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179505","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":"Return of genetic research results in 21,532 individuals with autism","authors":"","doi":"10.1016/j.gim.2024.101202","DOIUrl":"10.1016/j.gim.2024.101202","url":null,"abstract":"<div><h3>Purpose</h3><p>The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK (<span><span>SPARKforAutism.org</span><svg><path></path></svg></span>): a large recontactable cohort of people with autism in the United States. We also describe the process to return these clinically confirmed genetic findings.</p></div><div><h3>Methods</h3><p>We present results from microarray genotyping and exome sequencing of 21,532 individuals with autism and 17,785 of their parents. We returned LP and P (American College of Medical Genetics criteria) copy-number variants, chromosomal aneuploidies, and variants in genes with strong evidence of association with autism and intellectual disability.</p></div><div><h3>Results</h3><p>We identified 1903 returnable LP/P variants in 1861 individuals with autism (8.6%). 89.5% of these variants were not known to participants. The diagnostic genetic result was returned to 589 participants (53% of those contacted). Features associated with a higher probability of having a returnable result include cognitive and medically complex features, being female, being White (versus non-White) and being diagnosed more than 20 years ago. We also find results among autistics across the spectrum, as well as in transmitting parents with neuropsychiatric features but no autism diagnosis.</p></div><div><h3>Conclusion</h3><p>SPARK offers an opportunity to assess returnable results among autistic people who have not been ascertained clinically. SPARK also provides practical experience returning genetic results for a behavioral condition at a large scale.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 10","pages":"Article 101202"},"PeriodicalIF":6.6,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024001369/pdfft?md5=938c5b2d648bd9b26c56d2b4531acd45&pid=1-s2.0-S1098360024001369-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491692","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}