Genetics in Medicine最新文献

{"title":"Optical genome mapping improves clinical interpretation of constitutional copy-number gains and reduces their VUS burden","authors":"Avinash V. Dharmadhikari ,&nbsp;Alexander L. Markowitz ,&nbsp;Jennifer Han ,&nbsp;Dolores B. Estrine ,&nbsp;Dong Xu ,&nbsp;Katherine Ma ,&nbsp;Cindy Fong ,&nbsp;Bridget A. Fernandez ,&nbsp;Matthew A. Deardorff ,&nbsp;Ryan J. Schmidt ,&nbsp;Jianling Ji ,&nbsp;Gordana Raca","doi":"10.1016/j.gim.2025.101452","DOIUrl":"10.1016/j.gim.2025.101452","url":null,"abstract":"<div><h3>Purpose</h3><div>Genomic structure of copy-number gains is critical for their clinical interpretation but cannot be determined by chromosomal microarray (CMA) analysis, which does not provide information about chromosomal location and orientation of multiplied regions. We thus hypothesized that in CMA testing gains have higher probability than losses to be classified as variants of uncertain significance (VUS) and that structural information from optical genome mapping (OGM) may improve their interpretation.</div></div><div><h3>Methods</h3><div>Using a χ² test, we assessed the association between classification of copy-number variants as VUS and their type (gains vs losses) in a cohort of 4073 CMA cases. Thirty-three VUS gains involving disease-associated genes were characterized by OGM to evaluate if OGM data enable their more conclusive clinical interpretation.</div></div><div><h3>Results</h3><div>The proportion of variants reported as VUS compared with likely pathogenic/pathogenic was significantly higher for gains than losses, confirming their increased VUS burden. OGM successfully determined genomic structure for all 33 copy-number gains, showing that 26 of 33 were tandem duplications and 7 of 33 were complex rearrangements. Structural information facilitated clinical interpretation in majority of the cases; it supported benign nature for 27 of 33 gains and was inconclusive or supported pathogenic role for 6 of 33. An estimated 20% of reported VUS gains would not have been reportable if we had OGM data.</div></div><div><h3>Conclusion</h3><div>We illustrate a specific advantage of OGM compared with CMA: in addition to detecting both copy-number variants and balanced rearrangements, OGM improves clinical interpretation of copy-number gains by providing structural information and is thus expected to significantly decrease their VUS burden.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101452"},"PeriodicalIF":6.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002978","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":"10.1016/j.gim.2025.101388","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101388"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","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":"Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders","authors":"Eva Berger ,&nbsp;Robin-Tobias Jauss ,&nbsp;Judith D. Ranells ,&nbsp;Emir Zonic ,&nbsp;Lydia von Wintzingerode ,&nbsp;Ashley Wilson ,&nbsp;Johannes Wagner ,&nbsp;Annabelle Tuttle ,&nbsp;Amanda Thomas-Wilson ,&nbsp;Björn Schulte ,&nbsp;Rachel Rabin ,&nbsp;John Pappas ,&nbsp;Jacqueline A. Odgis ,&nbsp;Osama Muthaffar ,&nbsp;Alejandra Mendez-Fadol ,&nbsp;Matthew Lynch ,&nbsp;Jonathan Levy ,&nbsp;Daphné Lehalle ,&nbsp;Nicole J. Lake ,&nbsp;Ilona Krey ,&nbsp;Rami Abou Jamra","doi":"10.1016/j.gim.2024.101326","DOIUrl":"10.1016/j.gim.2024.101326","url":null,"abstract":"<div><h3>Purpose</h3><div>Heterozygous pathogenic variants in <em>NTRK2</em> (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of <em>NTRK2</em>-related disorders and to delineate the clinical presentation.</div></div><div><h3>Methods</h3><div>We reported an extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported.</div></div><div><h3>Results</h3><div>Our analysis led to splitting the cohort into 2 entities.</div></div><div><h3>Conclusion</h3><div>One group had variants in the cholesterol-binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A&gt;G p.(Tyr434Cys). These variants probably lead to upregulation of tropomyosin receptor kinase B activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity, and hyperphagia.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101326"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618656","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 ,&nbsp;Nasna Nassir ,&nbsp;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":"27 5","pages":"Article 101389"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","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":"Mainstreaming improved adoption of germline testing for Veterans Affairs patients with metastatic prostate cancer without exacerbating disparities","authors":"Maren T. Scheuner ,&nbsp;Katherine J. Hoggatt ,&nbsp;Paloma Sales ,&nbsp;Barbara Lerner ,&nbsp;Eva Ferino ,&nbsp;Morgan Danowski ,&nbsp;Ning Zhang ,&nbsp;Colin Purmal ,&nbsp;Samuel L. Washington III ,&nbsp;Michael M. Goodman ,&nbsp;Emily E. Ziegler ,&nbsp;Andrea J. Stoddard ,&nbsp;Carolyn Menendez ,&nbsp;Tori Foote ,&nbsp;Kerry Rowe ,&nbsp;Gina McWhirter ,&nbsp;Michael J. Kelley","doi":"10.1016/j.gim.2025.101383","DOIUrl":"10.1016/j.gim.2025.101383","url":null,"abstract":"<div><h3>Purpose</h3><div>To improve germline testing adoption for Veterans Affairs patients with metastatic prostate cancer (mPrCA), new delivery models were introduced to complement genetic consultation (traditional model), including mainstreaming where oncologists perform pre/posttest activities and a hybrid model where oncologists perform informed consent and then refer to genetics. We assessed germline testing adoption by delivery model.</div></div><div><h3>Methods</h3><div>We conducted a nationwide cohort study of mPrCA patients ascertained from May 3, 2021, to November 2, 2022, with follow-up through May 3, 2023. We assessed associations between patient and facility characteristics and having or completing germline test orders using Cox proportional hazards models.</div></div><div><h3>Results</h3><div>We identified 18,623 mPrCA patients. The average age was 73.9 years (SD, 8.3; range 35-102) with 59.6% non-Hispanic White and 28.9% non-Hispanic Black patients. The cumulative incidence of germline test orders was 13.7% over 2 years. Non-Hispanic Black patients were more likely than non-Hispanic White patients to have germline test orders (hazard ratio [HR], 1.28; 95% CI, 1.15-1.41) but less likely to complete their orders (HR, 0.81; 95% CI 0.72-0.91). Compared with non-Hispanic White patients, non-Hispanic Black patients were more likely to complete orders under the traditional model (HR, 1.40; 95% CI, 111-1.76), less likely under the hybrid model (HR, 0.62; 95% CI, 0.50-0.77) with no difference under the mainstream model.</div></div><div><h3>Conclusion</h3><div>Mainstreaming germline testing for mPrCA patients improved adoption without introducing disparities between non-Hispanic Black and White patients.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101383"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440636","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 ,&nbsp;Katelynn D. Stanley ,&nbsp;Laura E. MacMullen ,&nbsp;Ibrahim George-Sankoh ,&nbsp;Jing Wang ,&nbsp;Amy Goldstein ,&nbsp;Rui Xiao ,&nbsp;Marni J. Falk","doi":"10.1016/j.gim.2025.101386","DOIUrl":"10.1016/j.gim.2025.101386","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>Detailed cohort characterization highlighted that a recurrent deleted region involving <em>MT-ND5</em> (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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101386"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","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":"Smith-Lemli-Opitz syndrome: Clinical, biochemical, and genetic insights with emerging treatment opportunities","authors":"Amy Kritzer ,&nbsp;Rana Dutta ,&nbsp;Tiziano Pramparo ,&nbsp;Jolan Terner-Rosenthal ,&nbsp;Pamela Vig ,&nbsp;Robert D. Steiner","doi":"10.1016/j.gim.2025.101450","DOIUrl":"10.1016/j.gim.2025.101450","url":null,"abstract":"<div><div>Smith-Lemli-Opitz syndrome (SLOS), also known as RSH syndrome, is an inborn error of cholesterol biosynthesis first described in 1964. Since then, significant advances have been made in understanding its pathophysiology, both during fetal development and postnatally. Cholesterol is a crucial lipid in the body, especially in the central nervous system, which accounts for nearly 25% of the body’s total cholesterol. Cholesterol deficiency in SLOS can lead to congenital malformations and severe neurodevelopmental disabilities. The biochemical and genetic bases of SLOS have been elucidated. Reduced or absent 7-dehydrocholesterol reductase enzymatic activity results not only in cholesterol deficiency but also in accumulation of 7-dehydrocholesterol, 8-dehydrocholesterol, and toxic oxysterol metabolites, which contribute to the pathophysiology of SLOS and correlate variably with the severity of its clinical symptoms. Despite decades of research, the clinical recognition of SLOS remains challenging because of the condition’s multisystemic nature and noteworthy phenotypic variability. This review provides an up-to-date summary of major research advances in the study of SLOS with a focus on clinical manifestations and biochemical and genetic findings, which, taken together, facilitate recognition and diagnostic confirmation. Additionally, we recap past and current efforts in therapeutic development and offer guidance for disease management.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101450"},"PeriodicalIF":6.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984019","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":"Reconciling competencies in undergraduate medical genetics education: APHMG versus PCME competencies","authors":"Rachel D. Burnside ,&nbsp;Megan Boothe ,&nbsp;David H. Ledbetter ,&nbsp;Heather Stalker ,&nbsp;Petr Starostik ,&nbsp;Pamela Trapane","doi":"10.1016/j.gim.2025.101448","DOIUrl":"10.1016/j.gim.2025.101448","url":null,"abstract":"<div><h3>Purpose</h3><div>We wanted to understand whether there were gaps within and/or between the Association of Professors of Human and Medical Genetics (APHMG) and the Association of Pathology Chairs (APC) published competencies for undergraduate medical education pertaining to topics in medical and/or laboratory genetics.</div></div><div><h3>Methods</h3><div>This study compared and contrasted the APHMG and APC competencies related to genetics to identify gaps between and within each to inform the closure of those gaps in undergraduate medical education curriculum development for medical and laboratory genetics at the University of Florida.</div></div><div><h3>Results</h3><div>Gaps were identified within and between both documents, many relating to neoplasia for nonheritable cancers and various topics related to laboratory genetics, such as interpretation of results, principles of laboratory diagnostics, and explaining results to others.</div></div><div><h3>Conclusion</h3><div>APHMG and APC should consider the gaps identified in this study in future updates to their respective competencies. Additionally, medical school curriculum committees may also wish to consider addressing these gaps in the development of medical genetics curricula.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101448"},"PeriodicalIF":6.6,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993102","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":"Efficacy, safety, and tolerability of chenodeoxycholic acid (CDCA) in adult patients with cerebrotendinous xanthomatosis (RESTORE): A randomized withdrawal, double-blind, placebo-controlled, crossover phase-3 study","authors":"Yaz Y. Kisanuki ,&nbsp;Paulo R. Nobrega ,&nbsp;Ryan Himes ,&nbsp;Suman Jayadev ,&nbsp;John A. Bernat ,&nbsp;Vikram Prakash ,&nbsp;James B. Gibson ,&nbsp;Austin Larson ,&nbsp;Paulo Sgobbi ,&nbsp;Andrea E. DeBarber ,&nbsp;Edward Murphy ,&nbsp;Brian Fedor ,&nbsp;Cheryl Wong Po Foo ,&nbsp;Rana Dutta ,&nbsp;Michael Imperiale ,&nbsp;Will Garner ,&nbsp;Joanne Quan ,&nbsp;Pamela Vig ,&nbsp;P. Barton Duell ,&nbsp;Sarah Perez ,&nbsp;Wladimir Bocca Vieira de Rezende Pinto","doi":"10.1016/j.gim.2025.101449","DOIUrl":"10.1016/j.gim.2025.101449","url":null,"abstract":"<div><h3>Purpose</h3><div>Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in <em>CYP27A1</em>, resulting in sterol 27-hydroxylase deficiency and accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, diarrhea, cataracts, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The effects of CDCA withdrawal on CTX biomarkers and safety in adult patients were evaluated.</div></div><div><h3>Methods</h3><div>Patients (≥16 years) received CDCA 750-mg/day for 2 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for 2 4-week periods. Key endpoints included changes from baseline in CTX biomarkers (23S-pentol, cholestanol, 7αC4, 7α12αC4) and the proportion of patients requiring CDCA rescue during DB periods.</div></div><div><h3>Results</h3><div>CDCA withdrawal resulted in a 20-fold increase in 23S-pentol and increases in cholestanol (2.8-fold), 7αC4 (50-fold), and 7α12αC4 (14-fold). During the DB withdrawal periods, 61% of participants on placebo required rescue medication. CDCA treatment was well tolerated; the most common treatment-emergent adverse events were diarrhea and headache, most of them mild/moderate in severity and not considered treatment related.</div></div><div><h3>Conclusion</h3><div>CDCA withdrawal caused statistically significant increases in CTX biomarkers and necessitated rescue therapy in most participants. CDCA treatment is critical for control of biochemical abnormalities and helps avoid disease progression.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101449"},"PeriodicalIF":6.6,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964110","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":"Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status","authors":"Chris Odhams ,&nbsp;Hywel J. Williams","doi":"10.1016/j.gim.2025.101447","DOIUrl":"10.1016/j.gim.2025.101447","url":null,"abstract":"<div><h3>Purpose</h3><div>Identifying the pathogenic variant in a patient with rare disease (RD) is the first step in ending their diagnostic odyssey. De novo (Dn) variants affecting protein-coding DNA are a well-established cause of Mendelian disorders in patients with RD. Constrained coding regions (CCRs) are specific segments of coding DNA that are devoid of functional variants in healthy individuals.</div></div><div><h3>Methods</h3><div>We evaluated the diagnostic utility of incorporating combined Dn/CCR status into the variant prioritization cascade for patients with RD that have undergone genomic sequencing. Using the Genomics England 100,000 Genomes Project v12, we selected 3090 trios that have undergone diagnostic evaluation and been analyzed with an advanced Dn identification pipeline.</div></div><div><h3>Results</h3><div>Our analysis shows that the diagnostic rate increased from 71% in the full cohort to 87% for Dn/CCR variants. Of note, manual evaluation of the Dn/CCR variants from undiagnosed patients with clinical follow-up revealed a diagnosis for 13 further patients. This outcome increases the diagnostic rate for Dn/CCR variants to 91% and suggests that the application of this metric can prioritize diagnostic variants in undiagnosed patients.</div></div><div><h3>Conclusion</h3><div>We demonstrate the potential clinical utility of performing bespoke Dn analyses of patients with RD and for incorporating CCR information into the filtering cascade to prioritize pathogenic variants.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101447"},"PeriodicalIF":6.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998043","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}