Genetics in Medicine最新文献

{"title":"Cost-effectiveness of BRCA1/BRCA2 Variant Reclassification and Recontact for Hereditary Breast and Ovarian Cancer in the United States.","authors":"Gregory F Guzauskas, Sara M Berger, Robert O'Connor, Serra Kim, Scott Topper, Elizabeth Chao, Carolyn Horton, Lily Hoang, David L Veenstra, Wendy K Chung","doi":"10.1016/j.gim.2026.102697","DOIUrl":"10.1016/j.gim.2026.102697","url":null,"abstract":"<p><strong>Purpose: </strong>Reclassification of variants of uncertain significance in BRCA1/2 impact clinical management, health outcomes, and healthcare costs, raising questions about cost-effectiveness and optimal timing of reinterpretation. This study evaluated cost-effectiveness of BRCA1/2 variant reclassification strategies and how timing and duration influence outcomes.</p><p><strong>Methods: </strong>Using data from two independent commercial genetic testing laboratories, a decision analytic model was developed to simulate lifetime breast and ovarian cancer incidence, quality-adjusted life-years (QALYs), life years, and direct medical costs per 1,000 30-year-old women with prior BRCA1/2 testing. Reclassification strategies were modeled as annual or batches, with perpetual or fixed durations. A data-weighted cost of $200 was applied for reclassification and recontact for impactful reclassifications.</p><p><strong>Results: </strong>Incremental costs were estimated of $63 and $155 per 1,000 women with corresponding QALY gains of 0.0007 and 0.0032, resulting in incremental cost-effectiveness ratios of $86,723 and $48,554 respectively. Most incremental cancer reductions resulted from cascade testing. Batch-based reclassification strategies, particularly 5-year intervals with fixed endpoints, emerged as the most cost-effective.</p><p><strong>Conclusion: </strong>Structured, batch-based reclassification strategies with fixed endpoints are more cost-effective than perpetual schedules. This supports planned reclassification cycles to maximize health benefits and cost-effectiveness, conflicting with research supporting ongoing responsibility for reinterpretation without a defined time limit.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102697"},"PeriodicalIF":6.2,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818251","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 Fetal Fentanyl Syndrome: Additional evidence in support of a new human teratogen.","authors":"Álvaro Martín-Rodríguez, Adriana Gomes, Kristen Barbour, Kristen Wigby, Marilyn C Jones, Lynne M Bird, Miguel Del Campo","doi":"10.1016/j.gim.2026.102698","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102698","url":null,"abstract":"<p><strong>Purpose: </strong>Prenatal opioid exposure has inconsistently been associated with congenital anomalies. In 2023, fentanyl was proposed as a human teratogen in ten infants with documented exposure and a consistent pattern of abnormalities. Disrupted cholesterol biosynthesis was proposed as the pathogenetic mechanism.</p><p><strong>Methods: </strong>We evaluated 56 children aged 0-4 years with confirmed prenatal fentanyl exposure. We collected data on intrauterine exposures, dysmorphic features, congenital anomalies, neonatal course, feeding, growth and development, cholesterol precursors and genetic testing. We analyzed the role of co-exposures and specific features in predicting clinical and developmental outcomes. Associations between dysmorphology categories and outcomes were tested. Using diagnostic frameworks from fetal alcohol spectrum disorders, we evaluated criteria for a potential fetal fentanyl syndrome.</p><p><strong>Results: </strong>Among the enrolled patients, microcephaly, failure to thrive, feeding difficulties, and gastrostomy placement were common. A distinctive pattern of craniofacial dysmorphology was identified. Developmental delays affected 47% of individuals, and autism or high risk was identified in 50% of those screened. Genetic testing was non-contributory. Elevated cholesterol precursors were seen in some when tested in the first weeks of life. Dysmorphology severity was associated with microcephaly, failure to thrive, hypotonia, and gastrostomy use.</p><p><strong>Conclusion: </strong>Prenatal fentanyl exposure was associated with a recognizable pattern of dysmorphology, growth restriction, impaired brain development, and neurodevelopmental deficits. These findings support fentanyl as a human teratogen.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102698"},"PeriodicalIF":6.2,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812888","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":"P-KNN: joint calibration of multiple pathogenicity prediction tools streamlines variant classification.","authors":"Po-Yu Lin, Nadav Brandes","doi":"10.1016/j.gim.2026.102692","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102692","url":null,"abstract":"<p><strong>Purpose: </strong>Clinical guidelines for interpreting genetic variants in the context of Mendelian disease require converting the outputs of pathogenicity prediction tools into well-calibrated probabilities. However, the existing calibration method is only valid when pre-committing to one tool, preventing clinical laboratories from using multiple tools with complementary strengths. To lift this restriction, we introduce Pathogenicity K-Nearest Neighbors (P-KNN), a flexible method that jointly calibrates any set of tools.</p><p><strong>Methods: </strong>P-KNN represents each variant in a multidimensional space defined by tool scores and estimates the probability of pathogenicity based on the proportion of pathogenic neighbors. We compared P-KNN against standard single-tool calibration of multiple predictors and meta-predictors at four historical time points.</p><p><strong>Results: </strong>P-KNN outperforms standard calibration of single tools and meta-predictors in two aspects: i) overall evidence strength and ii) alignment of the calibrated probabilities with true pathogenicity frequencies. Additionally, the evidence from P-KNN keeps improving with the addition of newer tools. It also correctly integrates correlated computational and experimental evidence that is overestimated by existing protocols.</p><p><strong>Conclusion: </strong>P-KNN provides robust joint calibration for any set of pathogenicity prediction tools, thereby alleviating the constraint of pre-committing to a single predictor while enhancing statistical rigor and diagnostic yield. P-KNN is available via command line (https://github.com/Brandes-Lab/P-KNN) and precomputed scores (https://huggingface.co/datasets/brandeslab/P-KNN).</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102692"},"PeriodicalIF":6.2,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818224","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":"Patient and primary care clinician perspectives on polygenic risk scores for prostate cancer screening: a national qualitative study.","authors":"Marla L Clayman, Lilly Cheam, Christopher Gillespie, Ashley A Antwi, Ekaterina Anderson, Morgan E Danowski, Charles A Brunette, Vincent Song, Claire E Grant, Maren T Scheuner, Renda Soylemez Wiener, Jason L Vassy","doi":"10.1016/j.gim.2026.102696","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102696","url":null,"abstract":"<p><strong>Purpose: </strong>Polygenic risk scores (PRS) have been proposed as adjuncts to clinical risk prediction for prostate cancer, but little is known about patient-centered implementation of PRS-informed shared decision-making (SDM). We explored patients' and primary care clinicians' perspectives on using PRS in SDM about prostate cancer screening.</p><p><strong>Methods: </strong>We interviewed 2 national samples-male patients aged 40-60 years without prior prostate cancer, and primary care clinicians-within a national integrated healthcare system, about current screening practices, understanding of PRS, and anticipated impact on prostate-specific antigen (PSA) testing decisions. Transcripts were analyzed using a modified grounded theory approach.</p><p><strong>Results: </strong>We interviewed 21 primary care providers (MD/DO/NP/PA), 7 primary care nurses (RN/LPN), and 42 patients. Many clinicians saw utility in PRS for individualizing screening, especially for high-risk patients, though some did not anticipate changing their PSA testing approach. Clinicians anticipated patients would struggle to understand PRS, and some patients did misunderstand genetic risk and how to interpret results. Most patients did not anticipate delaying or reducing PSA testing after low-risk results, but many said high-risk results would motivate earlier or more frequent screening.</p><p><strong>Conclusion: </strong>Clinicians and patients anticipate acting on PRS results asymmetrically, favoring heightened screening for high-risk individuals but not reduced screening for those at low risk. Current PSA testing is already variable and not always guideline-concordant; introducing PRS will require additional strategies to promote high-quality SDM.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102696"},"PeriodicalIF":6.2,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808464","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":"Development of a simple clinical score to prioritize detection of severe alpha-1 antitrypsin deficiency with PiZZ genotype.","authors":"Yanzhen Cheng, Guillaume Butler-Laporte, Tomoko Nakanishi, Tianyuan Lu","doi":"10.1016/j.gim.2026.102690","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102690","url":null,"abstract":"<p><strong>Purpose: </strong>Alpha-1 antitrypsin deficiency (AATD) is caused primarily by the PiZZ genotype in SERPINA1 and remains underdiagnosed despite its association with severe lung and liver diseases. We aimed to develop and validate a clinical score using electronic health record (EHR) data to identify individuals more likely to carry the PiZZ genotype.</p><p><strong>Materials and methods: </strong>In the UK Biobank (UKB; N = 277,082), we developed the clinical score using logistic regression with variable selection based on medical conditions and anthropometric measurements. We evaluated its performance against random screening and targeted screening based on individual medical conditions in an independent UKB test dataset (N = 69,272) and the NIH All of Us Research Program (AoU; N = 162,198).</p><p><strong>Results: </strong>The optimized clinical score included chronic obstructive pulmonary disease, bronchiectasis, cirrhosis, and height. In the UKB test dataset and AoU, the score outperformed any single phenotype in identifying PiZZ genotype. Targeting individuals in the top 0.5% of the score increased screening efficiency by >95% compared with random screening and outperformed all medical condition-based screening strategies.</p><p><strong>Conclusion: </strong>Using readily available EHR data, the clinical score represents a starting point that may improve targeted case-finding and optimize allocation of diagnostic resources for AATD.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102690"},"PeriodicalIF":6.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792035","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":"Genomics-first association of pharmacogenomic risk phenotypes with adverse drug reactions in a healthcare-based population.","authors":"Rebecca I Torene, Ryley Uber, Tracy Brandt, Karyn Meltz Murphy, Eric A Wright, Kyle Retterer","doi":"10.1016/j.gim.2026.102691","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102691","url":null,"abstract":"<p><strong>Purpose: </strong>Pharmacogenomic (PGx) variation affects drug metabolism and adverse drug reaction (ADR) risk. While the Clinical Pharmacogenetics Implementation Consortium (CPIC) lists 573 actionable gene-drug pairs, large-scale evaluation of PGx-related ADRs remains limited. We performed a retrospective genomic-first analysis on genetic and electronic health record (EHR) data to assess PGx impact on ADR risk.</p><p><strong>Methods: </strong>We analyzed 226,053 individuals in the Geisinger MyCode cohort for 58 CPIC high-risk gene-drug associations spanning 11 genes. Genetic findings were linked to EHR allergy and medication discontinuation records.</p><p><strong>Results: </strong>Most individuals (211,920/226,053, 93.7%) had at least one actionable PGx phenotype and 44.4% (100,402/226,053) had an actionable phenotype conferring ADR risk and were prescribed a relevant medication. As individuals accumulate medication exposures, ADR incidence increases (Pearson's correlation=0.50, P<0.001). Individuals with risk phenotypes were more likely to have a documented allergy or ADR-related medication discontinuation (P<0.001, OR=1.4), and 3.9% (8,913/226,053) exhibited an ADR associated with personal PGx risk. We observed 36,194 ADRs across 27,546 individuals (12.2% of cohort); 10,719/36,194 (29.6%) occurred in individuals with relevant PGx phenotypes.</p><p><strong>Conclusion: </strong>Individuals exposed to more medications exhibit increased ADR rates. PGx further compounds ADR risk, and a portion of population ADR burden could possibly have been prevented through PGx-guided therapy.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102691"},"PeriodicalIF":6.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792114","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":"Short-term outcomes of a randomized, mixed-methods trial to improve hereditary cancer test results disclosure and follow-up communication with family.","authors":"Deborah L Cragun, Marleah Dean, Paige Phillips Hunt, Jason Beckstead, Anne Weidner, Tuya Pal","doi":"10.1016/j.gim.2026.102694","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102694","url":null,"abstract":"<p><strong>Purpose: </strong>This mixed-methods study evaluated an online, theory-guided family communication intervention (GeneSHARE) designed to increase initial sharing of genetic test results and follow-up communication with family members among individuals with a germline pathogenic or likely pathogenic variant (GPV) in a hereditary cancer gene.</p><p><strong>Methods: </strong>This randomized trial consisted of 528 participants with a GPV who self-reported having at least one untested, at-risk relative, of which a subset of participants were randomized into the GeneSHARE intervention and received resources designed to facilitate sharing of information and ongoing communication about hereditary cancer genes. All participants were asked to complete baseline and follow-up surveys, and a subset of participants were asked to complete an interview. Quantitative analyses compared communication outcomes across study groups, and qualitative interviews with a purposive subsample (N=10) examined the use of the GeneSHARE intervention.</p><p><strong>Results: </strong>Among the 442 participants who had not shared GPV results with all living, adult, blood-related relatives (i.e., first-degree, second-degree, and cousins) at risk of having the GPV, initial disclosure to at least one relative was significantly higher in the intervention group (29.5% vs. 20.8%; p=.042). More than half of all 528 participants followed up with at least one at-risk relative who had previously been informed of the GPV, though rates did not differ between groups (p=.161). Interviews showed that study emails prompted communication, and one-page handouts facilitated sharing. However, intervention delivery long after testing, login barriers, and limited emphasis on follow-up communication tempered the intervention's impact.</p><p><strong>Conclusion: </strong>The online intervention increased initial disclosure with at-risk relatives but did not enhance follow-up communication after initial disclosure. Findings highlight the value of integrating reminders to communicate with family into interventions, providing interventions earlier in care pathways, and expanding resources supporting ongoing family communication.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102694"},"PeriodicalIF":6.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792046","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":"Current Status of Genetic Testing and Mosaic Variant Assessment in Somatic Overgrowth and Vascular Anomalies: Insights from the Cancer Genomics Consortium Working Group.","authors":"Avinash V Dharmadhikari, Candace T Myers, Katherine A King, Bahareh Mojarad, Ying-Chen Claire Hou, Jie Liu, Patricia V Hernandez, Lea F Surrey, Kevin E Fisher, Adrienne Hammill, Denise Adams, Cate Paschal, Thuy L Phung, Catherine Cottrell, Yang Cao","doi":"10.1016/j.gim.2026.102686","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102686","url":null,"abstract":"<p><p>Somatic overgrowth and vascular anomalies are often present at birth but may only be clinically recognized later in life. Affected tissues commonly include veins and arteries, skin, adipose tissue, bone, and brain, resulting in a broad phenotypic spectrum encompassing vascular malformations, lipomatous and melanocytic nevus syndromes, skeletal abnormalities, and brain malformations. These conditions are typically caused by postzygotic variants present in a subset of cells due to mosaicism. The developmental timing and cell lineages involved determine the extent and distribution of affected tissues. While germline variants and their clinical consequences are well characterized, the impact of somatic mosaic variants remains less well understood. Because these variants are often absent or present at very low levels in blood, sensitive assays and analysis of affected tissues are required for detection. Advances in high-depth next-generation sequencing have enabled reliable identification of low-level mosaic variants and are central to the genetic diagnosis of these disorders. Numerous causative genes have been described, most notably activating variants in the PI3K-MTOR and RAS-MAPK pathways. Genetic testing provides diagnostic confirmation, informs prognosis and recurrence risk, and in some cases enables targeted therapy, such as alpelisib for PIK3CA-related overgrowth spectrum. However, testing strategies vary across laboratories in gene panel content, sequencing depth, and tissue requirements, leading to inconsistent diagnostic approaches. This review summarizes known causative genes, current testing methodologies, variant interpretation and reporting practices, major genomic alteration classes and recurrent hotspot variants, and highlights key knowledge gaps from clinical and laboratory perspectives.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102686"},"PeriodicalIF":6.2,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792110","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":"Hospital-wide implementation of inpatient first-tier rapid genome sequencing.","authors":"Tara L Wenger, Abbey A Scott, Lukas Kruidenier, Jennifer C Hayek, Anita E Beck, Penny Chow, Ian Glass, Margaret P Adam, James T Bennett, Katrina M Dipple, Megan Sikes, Jonathan Marquez, Kirsty McWalter, Britt Johnson, Alexandra C Keefe","doi":"10.1016/j.gim.2026.102685","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102685","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize the impact of hospital-wide implementation of inpatient first-tier rapid exome (rES) and rapid genome sequencing (rGS) at a large children's hospital.</p><p><strong>Methods: </strong>This single-center study examines the diagnostic yield of rES/rGS in 1000 children after hospital-wide implementation of inpatient first-tier rES/rGS across hospital units, and by clinical phenotypes at the time of consult over a 3.7 year period (5/5/22-1/26/26).</p><p><strong>Results: </strong>Our data demonstrate similar diagnostic rates as reported in prior studies for children in intensive care unit (ICU) settings (27.4-36.9%), and a slightly higher diagnostic rate in children admitted to non-ICU wards (43.1%; 125/290). The highest diagnostic rate across all clinical phenotypes present at consult was for \"faltering growth\" admissions in children admitted to non-ICU wards (65.2%; 30/46).</p><p><strong>Conclusion: </strong>This study provides descriptive data about clinical rES/rGS performed in 1000 children after hospital-wide implementation of first-tier rES/rGS. These data support implementation of first-tier rES/rGS for hospitalized children, including those outside of ICU settings, and potentially in the workup of \"faltering growth\".</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102685"},"PeriodicalIF":6.2,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792069","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":"Disease characteristics of SEPSECS deficiency: an international, retrospective, multicenter cohort study.","authors":"Benjamin Y Killam, Maria J Knol, Noelia Fradejas-Villar, Thilo S Chillon, George J G Ruijter, Ramon Bonte, Firdous Abdulwahab, Hesham Aldhalaan, Abdullah Alfaifi, Fowzan S Alkuraya, Hessa S Alsaif, Kaitlyn A Kiernan, Anupama K Puppala, Laura Baker, Leigh Batten, Aziza Chedrawi, Jennifer C Dempsey, Dan Doherty, Laurence Faivre, Vykuntaraju K Gowda, Mais O Hashem, Erfan Heidari, Masoud Garshasbi, Yuji Inaba, Kazuhiro Iwama, Maria Kinali, Rudolf Korinthenberg, Gaetan Lesca, Reza Maroofian, Naomichi Matsumoto, Benoît Mazel, Stanley F Nelson, Rinze F Neuteboom, C Ramona Nicolescu, Heather Olson, Annapurna Poduri, Masayuki Sasaki, David Schorling, Rebecca H Signer, Varunvenkat M Srinivasan, Abdullah Tamim, Ali R Tavasoli, Ehab Tous, Henna Tyynismaa, W Edward Visser, Antonio Vitobello, Victoria Vlachou, Martina Wilke, Hieab H H Adams, Lutz Schomburg, Ulrich Schweizer, Miljan Simonović, Serwet Demirdas","doi":"10.1016/j.gim.2026.102684","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102684","url":null,"abstract":"<p><strong>Purpose: </strong>Protein-altering gene variants in SEPSECS disrupt the biosynthesis of selenoproteins, leading to a spectrum of neurological diseases.</p><p><strong>Methods: </strong>We studied 27 individuals with biallelic SEPSECS variants, identifying 13 unreported gene variants. To better understand and diagnose the disorder, broad biochemical correlation of neurological symptoms, focused metabolomics, and structural and in vitro activity analyses were deployed.</p><p><strong>Results: </strong>Our results suggest three general clinical courses: (i) severe early-onset with cerebellar or cerebral atrophy, (ii) milder early-onset with gradual deterioration, and (iii) late-onset, mild disease. SEPSECS variants primarily affect the brain. In only one individual out of eight, thyroid hormone measurements suggested a defect of T4 to T3 conversion. Accompanied increase in glutathione and sulfur metabolites in plasma indicates elevated oxidative stress. Variants mapping to conserved N- and C-termini and catalytic site elicit SEPSECS misfolding, aggregation, thermal instability, and loss of function, that could ultimately lead to ferroptosis of neurons and perhaps oligodendrocytes. For differential diagnosis and monitoring therapeutic attempts, we recommend measuring levels of plasma selenium, glutathione and sulfur metabolites, GPX activity, and SELENOP. Given the pontine involvement in less than half of the cases, we suggest renaming the syndrome from PCH2D to SEPSECS-related neurodevelopmental disorder.</p><p><strong>Conclusion: </strong>Our study expands the understanding of SEPSECS-related neurodevelopmental disorders, highlighting the need for updated diagnostic criteria and potential treatment strategies.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102684"},"PeriodicalIF":6.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148764377","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}