Genetics in Medicine最新文献

{"title":"Not the end of the road: Achieving diagnoses following non-diagnostic exome sequencing: experiences at a clinical site of the Undiagnosed Diseases Network.","authors":"Rebecca C Spillmann, Nicole Walley, Kelly Schoch, Mohamad A Mikati, Vaidehi Jobanputra, Patrick Shea, Vandana Shashi","doi":"10.1016/j.gim.2026.102736","DOIUrl":"10.1016/j.gim.2026.102736","url":null,"abstract":"<p><strong>Purpose: </strong>Most participants who undergo exome sequencing (ES) remain undiagnosed. Since clinical ES reanalysis and clinical genome sequencing (GS) provide incremental diagnoses in only 5-15%, better resolution approaches to non-diagnostic ES are needed.</p><p><strong>Methods: </strong>Retrospective review of non-diagnostic NGS (ES/GS), at one site of the Undiagnosed Diseases Network (UDN), to assess the diagnostic approaches of ES/GS research reanalysis, clinical GS, non-ES/GS genetic testing and achieving diagnoses from clinical information.</p><p><strong>Results: </strong>77/192 (40%) participants with prior non-diagnostic NGS (ES/GS) obtained 80 diagnoses, including known disorders (n=50) and novel gene-disease associations (n=30). Research reanalysis of raw data from prior ES and UDN GS yielded the highest diagnoses (54%), followed by clinical ES/GS (27%), genetic testing other than ES/GS (11%) and clinical diagnoses (8%). Most causal variants were single nucleotide variants (SNVs- 78%) and most were coding (88%). Most (72%) genetic diagnoses should have occurred with prior ES; frequent reasons for diagnoses being overlooked were the prior laboratory not prioritizing: (a) novel gene variants (53%) and, (b) variants in known disorder genes due to perceived phenotypic mismatch (17%).</p><p><strong>Conclusions: </strong>An individualized approach to non-diagnostic NGS increased the diagnosis rate beyond reflexive GS. Most subsequent diagnoses and novel gene discoveries were from prioritization of variants amenable to ES.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102736"},"PeriodicalIF":6.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069454","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 Economic Costs of Genetic Counseling: A Combined Expert Perspective and Systematic Review.","authors":"Varinder Jeet, Julie Cigrang, Amanda Willis, Henry Cutler, Mary-Anne Young","doi":"10.1016/j.gim.2026.102739","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102739","url":null,"abstract":"<p><strong>Purpose: </strong>Genetic counseling (GC) is integral to personalized medicine, yet detailed estimates of its cost remain limited despite growing demand. This study systematically reviewed and synthesized evidence on GC costs, examined variations across settings, methodologies, and reported cost components.</p><p><strong>Methods: </strong>A systematic literature review was conducted following PRISMA guidelines across Embase and Ovid Medline databases. Studies were included if they reported GC costs. Data were extracted on study characteristics, methodologies, and reported costs. Costs were adjusted to 2024 values using OECD Consumer Price Index and converted to USD for comparability. A narrative synthesis approach was adopted due to methodological heterogeneity.</p><p><strong>Results: </strong>Nineteen of 1,487 screened studies met the inclusion criteria. Most relied on wage-based and time-based costing approaches, with limited use of systematic microcosting. Inflation-adjusted GC costs ranged widely ($72 to $1,970). Studies capturing only direct patient contact consistently reported lower costs than those incorporating indirect activities.</p><p><strong>Conclusion: </strong>Published GC costs vary markedly due to differences in costing scope, methodology, and healthcare systems. Standardized costing frameworks are needed to improve comparability across studies and support accurate planning, resource allocation, service design, and evaluation in genomic medicine.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102739"},"PeriodicalIF":6.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069490","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":"Universal versus guideline-based germline multigene panel testing in solid tumors: Diagnostic yield, variant of uncertain significance burden, and clinical actionability - A systematic review with meta-analysis.","authors":"Imad Barjij, Sarah Naciri, Sihame Lkhoyaali, Saoussane Kharmoum, Hanane Inrhaouen, Ibrahim Elghissassi, Saber Boutayeb, Hind Mrabti, Hassan Errihani","doi":"10.1016/j.gim.2026.102733","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102733","url":null,"abstract":"<p><strong>Purpose: </strong>To compare diagnostic yield, variant of uncertain significance (VUS) burden, and clinical actionability of universal versus guideline-based germline multigene panel testing in adults with solid tumors.</p><p><strong>Methods: </strong>PubMed, Embase, Web of Science, and Scopus were searched from inception to January 30, 2026. Studies reporting germline multigene testing outcomes in adult solid tumor populations were included. Risk of bias was assessed with validated tools. Proportions were pooled using random-effects models.</p><p><strong>Results: </strong>Among 144 included studies, 14 formed the comparative evidence set. In unselected cohorts, pooled diagnostic yield was 0.13 (95% confidence interval [CI], 0.11-0.17; I² = 98%), and pooled VUS burden was 0.40 (95% CI: 0.33-0.48; I² = 97%). In a two-study synthesis, National Comprehensive Cancer Network (NCCN) criteria sensitivity was 0.72 (95% CI: 0.67-0.76), indicating that approximately 28% of individuals with pathogenic or likely pathogenic variants would not meet the tested criteria.</p><p><strong>Conclusion: </strong>Universal germline multigene testing detects additional hereditary cancer predisposition beyond phenotype-based criteria but increases uncertain findings. Standardized actionability definitions and prospective comparative studies are needed to guide implementation.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102733"},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038132","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":"Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum.","authors":"Raman Kumar, Alison Gardner, Rudrarup Bhattacharjee, Shreya Agarwala, Clare L van Eyk, Mark A Corbett, Renee Carroll, Thessa Kroes, Tarin Ritchie, Rebekah de Nys, Danielle Mazurkiewicz, Wu Bing, Elizabeth E Palmer, Michael Field, Jolijn J A Verseput, Bert B A de Vries, Alexander J M Dingemans, Qi Zhang, Fuyi Li, Francois Bernier, Julie Lauzon, Robert Śmigiel, Juan Darío Ortigoza-Escobar, Angeles García-Cazorla, Alejandra Darling, Cornelius F Boerkoel, Stephanie Huynh, Gregory Costain, Tjakko J van Ham, Esmee Kasteleijn, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Ype Elgersma, Yvette van Ierland, Danielle Veenma, Dimitar Azmanov, Allison Goetsch Weisman, Carlos E Prada, Sandhya Parkash, Andrea L Rideout, W S Kerstjens-Frederikse, Jaime Vengoechea, Jan-Christoph Schoene-Bake, Francoise Devillard, Jasper van der Smagt, Noor A A Giesbertz, Andrew E Fry, Jana Jezkova, Antje Kampmeier, Alma Kuechler, Ute Grasshoff, Miriam Bertrand, Scott E Hickey, Jesse M Hunter, Mackenzie V Marr, Juliette Dupont, Stefania Bigoni, Alessandra Ferlini, Rita Selvatici, Nicolas Chatron, Gaetan Lesca, Louis Januel, Massimiliano Rossi, Curtis Rogers, Jessica M Davis, Fiona McKenzie, Felix Marbach, Laura Gieldon, Wolfgang M Schmidt, Amina Paquay, Reginald E Bittner, Simone Mahal, Günther Bernert, Ingrid Sinnerbrink, Linda Goodwin, Sandra Cooper, Natalja Bannink, Lachlan A Jolly, Julie McGaughran, Alexis Bosman, Rebecca Hernan, Wendy K Chung, Irene Valenzuela, Ivon Cuscó, Agatha Schlüter, Aurora Pujol, Luis Alberto Pérez-Jurado, Jozef Gecz","doi":"10.1016/j.gim.2026.102734","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102734","url":null,"abstract":"<p><strong>Purpose: </strong>TRranscription EXport (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, mRNA export, genome stability, cell differentiation and survival. We aimed to determine if variation in the TREX subunits, in addition to THOC2 and THOC6 genes, caused Neurodevelopmental Disorders.</p><p><strong>Methods: </strong>Through international collaboration we aggregated and assessed 40 individuals with high impact variants across four TREX subunit coding genes: THOC2 and THOC6 (known disease genes), and THOC7 and ALYREF (THOC4) (candidate disease genes).</p><p><strong>Results: </strong>On the background of considerable heterogeneity of neurodevelopmental and clinical outcomes, we noted that all TREX subunit variants impact cognitive functioning and development, speech and the respiratory systems as well as result in recognisable facial dysmorphism. We identified and studied five recurrent THOC2 variants, which give overlapping yet variable clinical presentations, including severe perinatal lethal arthrogryposis multiplex congenita (AMC). Using cells from 13 affected individuals, we show that their TREX subunit variants are generally partial loss of function (LoF), which alter protein localisation, protein stability, protein-protein interactions or delete internal or C-terminal protein functional domains. Cells from affected individuals from across all four TREX subunits studied show consistent, yet variable accumulation of DNA damage.</p><p><strong>Conclusion: </strong>The molecular, cellular and in silico data with the clinical presentations define a TREX spectrum disorder due to functional variation across multiple TREX subunits.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102734"},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038068","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":"Rescue of Proteus syndrome lethality in mice with prenatal miransertib treatment.","authors":"Shaima Raji Abdul Rahiman Sirajuddeen, Marjorie J Lindhurst, Megan Detels, Nathaniel Laughner, Jennifer Johnston, Lauren R Brinster, Leslie G Biesecker","doi":"10.1016/j.gim.2026.102732","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102732","url":null,"abstract":"<p><strong>Purpose: </strong>Proteus syndrome is caused by constitutive AKT1 activation, resulting in severe overgrowth and tumor susceptibility. We developed a mouse model, featuring endogenously regulated, mosaic expression of the Akt1 c.49G>A, p.(Glu17Lys) (Akt1 E17K) variant. Prior results showed that ubiquitous Akt1^E17K expression causes embryonic lethality. We hypothesized that a therapeutic effect of a small molecule could rescue the embryonic lethality and serve as a screen for the therapeutic potential of an agent.</p><p><strong>Methods: </strong>We first tested whether miransertib, an allosteric pan-AKT inhibitor can cross the placental barrier. To assess embryonic survival to birth, dams from timed matings between ACTB-Cre and Akt1^WT/flx mice were dosed at specific gestational time points.</p><p><strong>Results: </strong>Mice treated at 60 or 90 mg/kg/day showed a significantly increased, p=0.0003, proportion of neonatal survival (15/63 compared to 6/152). A startling observation was that several mutant βA-Akt1^WT/flx mice were not only born alive but were apparently healthy until nearly 18 months of age without postnatal miransertib treatment and showed a high variant allele fraction in nearly all tissues.</p><p><strong>Conclusion: </strong>Dose-dependent rescue of βA-Akt1^WT/flx embryos using miransertib validates the drug's potential as a therapeutic candidate. The βA-Akt1^WT/flx mouse model can serve as a platform for rapid preclinical drug testing for Proteus syndrome.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102732"},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038106","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":"Who Are We Missing: Examining Health Insurance Coverage for Expanded Carrier Screening.","authors":"Candice Shi, MaryAnn Campion, Carly M Smith, Jenna Kornish","doi":"10.1016/j.gim.2026.102729","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102729","url":null,"abstract":"<p><strong>Purpose: </strong>Our study aimed to examine the effect of coverage criteria utilized by payors on the detection of an individual's carrier status.</p><p><strong>Methods: </strong>We performed a retrospective chart review of patients and their reproductive partners at a single institution who had a positive carrier screening result to collect demographic information, carrier screening results, and family medical history. We estimated the proportion of individuals who would not have met coverage criteria for carrier screening that would detect their full carrier status based on policies used by major healthcare payors in California.</p><p><strong>Results: </strong>Of the participants with positive carrier screening results, 93% would not have had their full carrier status detected if carrier screening following payor policies was elected instead of expanded carrier screening. The highest proportion of participants who would not have their carrier status detected were of East Asian ethnicity (94%) and White ethnicity (94%), followed by South Asian ethnicity (93%) and Hispanic ethnicity (93%).</p><p><strong>Conclusion: </strong>Payors generally rely on ethnicity and family history to determine what type of carrier screening a policyholder is eligible for, therefore missing a significant portion of people who are heterozygous for pathogenic variants. These criteria contribute to insufficient, unequal and limited carrier screening strategies.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102729"},"PeriodicalIF":6.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016663","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":"Shared founder effect of the LIPH variant underlies the high prevalence of autosomal recessive woolly hair/hypotrichosis in Korea and Japan.","authors":"Hyun-Tae Shin, Ohsang Kwon, Jin Park, Young Lee, Hyunsun Park, Yong Hyun Jang, Bark-Lynn Lew, Jee Woong Choi, Byeong Cheol Park, Min Seong Kim, Moon-Bum Kim, Hyun-Ji Ryu, Mi Eun Choi, Hye Young An, Kyung Hee Jung, Ji Won Byun, Jeonghyun Shin, Gwang Seong Choi","doi":"10.1016/j.gim.2026.102720","DOIUrl":"10.1016/j.gim.2026.102720","url":null,"abstract":"<p><strong>Purpose: </strong>Autosomal Recessive Woolly Hair/Hypotrichosis (ARWH) due to LIPH variants is common in East Asia, especially in Japan, but its genetic architecture in the Korean population and the ancestral origin of these variants remain uncharacterized. This study aimed to define the molecular spectrum of LIPH variants in a Korean cohort and to trace the history of East Asian founder variants.</p><p><strong>Methods: </strong>We analyzed pathogenic variant frequencies from public genomic databases and performed exome sequencing and haplotype analysis on 32 Korean ARWH participants from independent families.</p><p><strong>Results: </strong>The p.Cys246Ser founder variant was highly prevalent in both Korea and Japan. Haplotype analysis confirmed an identical ancestral origin, providing strong evidence for a shared founder effect between Korea and Japan. This shared genetic history is the primary driver of the high prevalence of ARWH, estimated at 1 in 7092 in Korea and 1 in 4975 in Japan. Furthermore, we identified p.Asp207His as a newly identified Korean-specific founder variant.</p><p><strong>Conclusion: </strong>The high prevalence of LIPH-associated ARWH in East Asia is explained by a shared founder effect of the p.Cys246Ser variant between Korea and Japan, revealing a significant public health burden. The discovery of a previously unreported Korean founder variant further refines the population-specific genetic history of this disorder.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102720"},"PeriodicalIF":6.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989816","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":"Precision Health Genetic Screening: Protocol and results categories for a clinical population genetic screening program.","authors":"Kimberly S Foss, Rachel Phillips, Kristine J Kuczynski, R Jean Cadigan, Laura V Milko, Julianne M O'Daniel, Sabrina N Powell, Bradford C Powell, Megan C Roberts, Elizabeth K Hutchins, Michael C Adams, Grace Leon-Lozano, Karen E Weck, Jonathan S Berg, Gail E Henderson","doi":"10.1016/j.gim.2026.102726","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102726","url":null,"abstract":"<p><strong>Purpose: </strong>As population genetic screening (PGS) gains traction with declining genetic sequencing costs and increased interest in personal health genetics, multiple diverse programs are being implemented throughout the nation. We introduce a clinical program embedded in a large healthcare system.</p><p><strong>Methods: </strong>The UNC Precision Health Genetic Screen (PHGS) is a clinical PGS program analyzing three CDC Tier 1 genetic conditions: Hereditary Breast and Ovarian Cancer syndrome (HBOC), Lynch syndrome (LS), and Familial Hypercholesterolemia (FH).</p><p><strong>Results: </strong>From the summer of 2021 through March 2026, the UNC PHGS returned 348 test results: 331 negatives and 16 positives (8 HBOC, 4 LS, 4 FH). One negative result was later reclassified from an unreported Variant of Uncertain Significance (VUS) to Likely Pathogenic (increasing to 17 positive results and FH to 5). The PHGS team developed internal results categories to contextualize results with reported personal and family history; these 6 categories help indicate how reassuring negative results could be to the individual. Negative results were \"aligned with history provided\" (n=208), \"unaligned with family history\" (n=113, later 112), or \"unaligned with personal history\" (n=11). Positive results were \"unaligned with history provided\" (n=7), \"aligned with family history\" (n=9, later 10), or \"aligned with personal history\" (n=0).</p><p><strong>Conclusion: </strong>As PGS programs monitor their clinical outcomes, it will be important to categorize both positive and negative results in terms that reflect the underlying chance of a monogenic condition, to identify potential participants for whom clinical diagnostic testing would have been warranted, and reduce the potential for false reassurance among those with negative screening results.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102726"},"PeriodicalIF":6.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008378","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":"Bi-allelic GAD2 variants cause a rare developmental encephalopathy with early-onset seizures.","authors":"Mathijs B van der Lei, Matthias De Wachter, Claudio Peter D'Incal, Ayu Scott, Elke Calus, Magali M L Van der Veken, Ellen Elinck, Kevin De Man, Yousra El Ouaamari, Anne Schepers, Ligia Mateiu, Debby Van Dam, An-Sofie Schoonjans, Emma Wakeling, Nour Elkhateeb, Laila Selim, Sabine M Hölter, Susan Marschall, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Reza Maroofian, Berten Ceulemans, Anna C Jansen, R Frank Kooy","doi":"10.1016/j.gim.2026.102724","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102724","url":null,"abstract":"<p><strong>Purpose: </strong>GAD67 and GAD65, encoded by GAD1 and GAD2, respectively, are the two isoforms of glutamic acid decarboxylase (GAD), the enzyme responsible for γ-aminobutyric acid (GABA) synthesis. Pathogenic variants in GAD1 cause a severe developmental and epileptic encephalopathy, whereas GAD2 has not previously been implicated in human disease.</p><p><strong>Methods: </strong>We identified four individuals from three unrelated families with bi-allelic GAD2 loss-of-function variants. Clinical and genetic findings were combined with functional analysis of the variants. To further establish causality, we characterized a GAD65 knockout (GAD65-/-) mouse model for seizures, behavior and transcriptomic changes.</p><p><strong>Results: </strong>All individuals presented with early-onset epilepsy, developmental delay, mild to moderate intellectual disability and autism spectrum disorder. Seizures were most severe during infancy and appeared to diminish with age. EEG showed preserved background activity without consistent epileptiform abnormalities, and brain MRI revealed only minimal structural changes. All variants resulted in truncated protein products, supporting a recessive loss-of-function mechanism. GAD65-/- mice were viable and developed spontaneous seizures, with onset as early as four weeks and showed increased susceptibility to pentylenetetrazole (PTZ) induced seizures. These mice also exhibited increased locomotor, anxiety-like and repetitive behaviors, as well as social deficits and impairments in spatial learning and memory. Transcriptomic profiling revealed dysregulation of metabolic and mitochondrial pathways implicated in epilepsy.</p><p><strong>Conclusion: </strong>Our findings firmly establish GAD2 as a disease gene implicated in developmental encephalopathy with early-onset seizures. The concordance between the human phenotype and the characteristics of the knockout mouse model emphasizes the pivotal role of GAD2 in neurodevelopment and epilepsy.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102724"},"PeriodicalIF":6.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148967888","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":"Germline ATM Testing in Hereditary Cancer Syndromes: Feedback from a Five-Year Center Cohort.","authors":"Iulian Ban, Lamisse Mansour-Hendili, Ana Maria Navarro, Karen Baudry, Tatiana Kogut-Kubiak, Xavier Mialhe, Carole Corsini, Pascal Pujol, Jérôme Solassol","doi":"10.1016/j.gim.2026.102719","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102719","url":null,"abstract":"<p><strong>Purpose: </strong>Germline ATM pathogenic or likely pathogenic (P/LP) variants are increasingly recognized as clinically relevant in hereditary cancer predisposition, their integration into routine testing remains heterogeneous across countries. We describe the prevalence, tumor spectrum and relative risk associated with germline ATM P/LP variants in individuals with breast and pancreatic cancer.</p><p><strong>Methods: </strong>We conducted a five-year retrospective (2019-2025) reanalysis of the ATM gene in 1,707 probands tested with hereditary breast and ovarian cancer (HBOC) or pancreatic cancer panels in our center. For all probands that underwent targeted ATM reanalysis, relative risks (RR) and odds ratios (OR) were calculated. Family-based segregation was performed when possible.</p><p><strong>Results: </strong>Targeted ATM re-analysis identified 33 additional probands with P/LP variants, increasing diagnostic yield from 7.3% to 9.1% in HBOC and from 4.3% to 9.7% in pancreatic cancer. Among 22 breast-cancer probands, mean age at diagnosis was 47 years. Case-control comparison yielded OR 3.85 (95% CI 2.43-6.08; P=8.5×10^-9) for breast cancer and OR 15.81 (95% CI 6.31-39.66; P=4.0×10^-9) for pancreatic cancer.</p><p><strong>Conclusion: </strong>This work strengthens the role of ATM in cancer predisposition panels and supports its inclusion in French national hereditary cancer panel recommendations, together with implementation of appropriate surveillance and counseling for individuals harboring ATM P/LP variants.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102719"},"PeriodicalIF":6.2,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944224","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}