Genetics in Medicine最新文献

{"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 A 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":"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 sequencing (rES) and rapid genome sequencing (rGS) at a large children's hospital.</p><p><strong>Methods: </strong>This single-center study examined 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 consultation over a 3.7-year period (May 5, 2022 to January 26, 2026).</p><p><strong>Results: </strong>Our data demonstrate similar diagnostic rates to those 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 (125 of 290 [43.1%]). The highest diagnostic rate across all clinical phenotypes present at consultation was for \"faltering growth\" admissions in children admitted to non-ICU wards (30 of 46 [65.2%]).</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 the implementation of first-tier rES/rGS for hospitalized children, including those outside 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":"Transmission ratio distortion of NF1 variant alleles in familial neurofibromatosis type 1.","authors":"Yang Pei, Andrew Browne, Edgar Creus-Bachiller, Conxi Lázaro, Elisabeth Castellanos Perez, Meena Upadhyaya, Vincent M Riccardi, Margaret R Wallace, Anne Goriely","doi":"10.1016/j.gim.2026.102682","DOIUrl":"10.1016/j.gim.2026.102682","url":null,"abstract":"<p><strong>Purpose: </strong>Neurofibromatosis type 1 (NF1) is a common autosomal dominant tumor-predisposition syndrome (approximately 1:3000 worldwide), involving pigmentary, skeletal, and neurodevelopmental features, and lifelong tumor risk. Although NF1 has been traditionally assumed to follow Mendelian transmission, our analyses reveal a consistent deviation from this expectation.</p><p><strong>Methods: </strong>We analyzed transmission patterns in 322 NF1 families across 4 well-characterized cohorts, applying strict inclusion criteria to minimize ascertainment bias and to exclude possible mosaic cases. Subsampling and large-scale random downsampling analyses were used to assess whether cohort size or other confounders could account for the observed transmission pattern.</p><p><strong>Results: </strong>Among 701 offspring, 61.1% were diagnosed with NF1, significantly exceeding the 50% expected under Mendelian inheritance (P = 5 × 10^-9). This robust transmission ratio distortion was present in both female (62.8%) and male (58.5%) transmitters. We propose that this pattern is most consistent with clonal selection of NF1-null cells within the early embryonic germline, a mechanism grounded in established NF1 tumor biology but not previously implicated in patterns of inheritance.</p><p><strong>Conclusion: </strong>Our findings identify a previously unrecognized feature of NF1 genetics and suggest germline selection as a potential driver of transmission ratio distortion, with implications for clinical practice, prenatal diagnostics, and reproductive counseling.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102682"},"PeriodicalIF":6.2,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712097","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":"ACMG/AMP variant classification specifications from the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel","authors":"Lacey Smith,&nbsp;Emily Bonkowski,&nbsp;Anna Prentice,&nbsp;Stacey Cohen,&nbsp;Laina Lusk,&nbsp;Shridhar Parthasarathy,&nbsp;Brendan Burns,&nbsp;Elizabeth Butler,&nbsp;Yanmin Chen,&nbsp;Kathleen Dady,&nbsp;Sarah Dugger,&nbsp;Alexander Ing,&nbsp;Rhonda Lassiter,&nbsp;David Lewis-Smith,&nbsp;Maureen Mulhern,&nbsp;Jimmy N.H. Nguyen,&nbsp;Jonathan Olival,&nbsp;Samin A. Sajan,&nbsp;Christopher H. Thompson,&nbsp;Alfred L. George Jr.,&nbsp;Heather C. Mefford","doi":"10.1016/j.gim.2026.102615","DOIUrl":"10.1016/j.gim.2026.102615","url":null,"abstract":"<div><h3>Purpose</h3><div>Pathogenic variants in <em>SCN1A</em>, <em>SCN2A</em>, <em>SCN3A</em>, <em>SCN8A</em>, and <em>SCN1B</em> have been associated with a spectrum of epilepsy and neurodevelopmental disorders. We created a Clinical Genome Resource variant curation expert panel and adapted the American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations for sequence variant classification for each of these genes.</div></div><div><h3>Methods</h3><div>We convened a multidisciplinary panel and evaluated current recommendations for their applicability. Then, we generated specifications based on clinical, bioinformatic, and functional data and piloted modified criteria on 37 variants.</div></div><div><h3>Results</h3><div>Our pilot consisted of variants across the spectrum of prior classifications (eg, pathogenic, benign, and variant of uncertain significance) and a range of variant types (eg, missense, nonsense, frameshift, and intronic). Through iterative discussion, our specifications notably include: (1) the importance of epilepsy syndrome classification and phenotyping, (2) optimization of population frequency thresholds, (3) the use of paralogous genes when considering prior pathogenic variants at corresponding positions, and (4) guidance on interpreting functional data, among other modifications.</div></div><div><h3>Conclusion</h3><div>Adopting modified variant curation specifications for <em>SCN1A</em>, <em>SCN2A</em>, <em>SCN3A</em>, <em>SCN8A</em>, and <em>SCN1B</em> optimizes variant classification based on evolving knowledge of sodium channel genes. Obtaining an accurate genetic diagnosis has both clinical and personal utility for individuals living with epilepsy and neurodevelopmental disorders, particularly as precision therapeutics become more widely available.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 8","pages":"Article 102615"},"PeriodicalIF":6.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143061","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":"VCP variants cause Adams-Oliver syndrome with or without pulmonary hypertension","authors":"Anna Lehman,&nbsp;Sana Ahmed,&nbsp;Arezoo Mohajeri,&nbsp;Alison M. Berezuk,&nbsp;Dhiraj Mannar,&nbsp;Spencer Cholak,&nbsp;Katharine S. Tuttle,&nbsp;James T. Bennett,&nbsp;Jeanine Aparecida Magno,&nbsp;Mark Hannibal,&nbsp;Gordana Kovacevic,&nbsp;Vladimir Kuburović,&nbsp;M.E. Suzanne Lewis,&nbsp;Oana Moldovan,&nbsp;Zoe Nelson,&nbsp;Salmo Raskin,&nbsp;Anthony M. Vandersteen,&nbsp;Jared C. Roach,&nbsp;Sriram Subramaniam,&nbsp;Millan S. Patel","doi":"10.1016/j.gim.2026.102579","DOIUrl":"10.1016/j.gim.2026.102579","url":null,"abstract":"<div><h3>Purpose</h3><div>Adams-Oliver syndrome (AOS) is a genetically heterogeneous disorder with cardinal features of aplasia cutis congenita and terminal limb reduction defects. A minority of individuals with AOS develop potentially lethal pulmonary hypertension (PH) in infancy, a subgroup that has been refractory to genetic explanation.</div></div><div><h3>Methods</h3><div>We studied a cohort of individuals with AOS and no genetic diagnosis by genome and exome sequencing. We characterized rare, identified substitution variants in valosin-containing protein (VCP) in vitro using ATP hydrolysis, cryogenic-electron microscopy, thermal stability, and response to CB-5083, a VCP inhibitor.</div></div><div><h3>Results</h3><div>We report a new genetic etiology for AOS in 6 families with PH and 1 family without it. We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling. Additionally, we find that CB-5083 inhibits the overactive ATP hydrolysis. Review of published cases of AOS with PH suggests that pulmonary vein stenosis is the most common mechanism. Clinical risk factors for PH in AOS include cutis marmorata telangiectatica congenita, prominent dilated subcutaneous veins and intrauterine growth restriction.</div></div><div><h3>Conclusion</h3><div>We identify the prevalent genetic cause of pulmonary hypertension in AOS and highlight a potential therapeutic approach.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 8","pages":"Article 102579"},"PeriodicalIF":6.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147672526","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":"Retrospective study of foramen magnum development in patients with achondroplasia starting vosoritide before age 3.","authors":"Marie Nakagawa, Natsuho Adachi, Motoyuki Umekawa, Hirotaka Hasegawa, Keita Okada, Hiroyuki Tanaka","doi":"10.1016/j.gim.2026.102666","DOIUrl":"10.1016/j.gim.2026.102666","url":null,"abstract":"<p><strong>Purpose: </strong>Achondroplasia (ACH) is a monogenic skeletal dysplasia caused by gain-of-function variants in FGFR3, leading to impaired endochondral ossification and foramen magnum stenosis. Although vosoritide promotes endochondral ossification, its effects on foramen magnum development remain unclear. In this study, we evaluated the impact of early vosoritide administration on foramen magnum development in infants and young children with ACH, using longitudinal magnetic resonance imaging.</p><p><strong>Methods: </strong>This retrospective, single-center case series included 9 patients who initiated vosoritide before age 3 years. Serial head magnetic resonance imaging scans were analyzed. The anteroposterior and transverse diameters of the foramen magnum were measured and compared with reference curves from untreated ACH cohorts. The severity of stenosis was assessed using the ACH foramen magnum score (AFMS). Correlations between changes in body height standard deviation score and foramen magnum dimensions were assessed.</p><p><strong>Results: </strong>Vosoritide was initiated at a median age of 4 months, with a mean treatment duration of 2.5 years. Compared with untreated cohorts, steeper growth rates were observed in 8 of the 9 patients for the anteroposterior diameter and in all patients for the transverse diameter. Most patients remained at AFMS 1 or 2. One patient progressed to AFMS 3 and underwent decompression surgery at age 11 months. No significant correlation was identified between changes in body height standard deviation score and foramen magnum diameter.</p><p><strong>Conclusion: </strong>Early vosoritide administration may promote foramen magnum development in infants and young children with ACH, independently of systemic growth effects. Even when height improvement is limited, enhancement of foramen magnum growth may be clinically relevant.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102666"},"PeriodicalIF":6.2,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578412","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":"Surveillance adherence and clinical findings in children with confirmed or familial TP53 variants: the Swedish multicenter constitutional TP53 study (SWEP53).","authors":"Alexander Sun Zhang, Meis Omran, Joakim Wille, Torben Ek, Magnus Sabel, Niklas Pal, Trausti Óskarsson, Per Kogner, Gustaf Ljungman, Emma Tham, Svetlana Bajalica-Lagercrantz","doi":"10.1016/j.gim.2026.102643","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102643","url":null,"abstract":"<p><strong>Purpose: </strong>Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caused by germline TP53 variants. Guidelines recommend intensive surveillance from birth to enable early tumor detection. Pediatric adherence, germline testing behaviors, false-positive rates, and downstream work-up remain unstudied. Understanding these factors is essential to optimize surveillance and mitigate harm.</p><p><strong>Methods: </strong>Pediatric SWEP53 (2016-2024) was a Swedish nationwide, prospective, multicenter surveillance study of individuals <18 years with a confirmed or 50% risk of a pathogenic or likely pathogenic germline TP53 variant (n = 37). Surveillance comprised quarterly clinical examination, abdominal ultrasound, and urine steroid profiling.</p><p><strong>Results: </strong>Surveillance adherence ranged from 77% to 97% and was lowest for urine sampling due to limited time and motivation. Germline testing occurred frequently within the first year (p < 0.001). One of two cancers diagnosed during the study was through surveillance. The false-positive rate was 12% per person-year, primarily triggered by clinical examinations (60%) and abdominal ultrasounds (27%). Overall, 35% experienced at least one false positive (median time: 1.3 years), prompting imaging or specialist referral; one case required invasive diagnostics.</p><p><strong>Conclusion: </strong>Pediatric LFS surveillance shows high adherence and early germline TP53 testing uptake, but notable false-positive rates. These results may guide clinical handling and surveillance guidelines.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102643"},"PeriodicalIF":6.2,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404540","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":"An integrated cardiometabolic genetic testing program in a predominantly Hispanic population within a community setting","authors":"Bo Yuan,&nbsp;Layla A. Abushamat,&nbsp;Stacey Pereira,&nbsp;Surya Narayan Mulukutla,&nbsp;Grace E. Tietz,&nbsp;Eric Venner,&nbsp;Sara E. Kalla,&nbsp;Breanna Lee,&nbsp;Donna Muzny,&nbsp;Ginger Metcalf,&nbsp;Mullai Murugan,&nbsp;Sarah H. Elsea,&nbsp;Senkottuvelan Kadirvel,&nbsp;Lele Li,&nbsp;Joshi Stephen,&nbsp;Shengfeng Xu,&nbsp;Victoria Yi,&nbsp;Monica Sulit,&nbsp;Christie L. Kovar,&nbsp;Kimberly Walker,&nbsp;Ashok Balasubramanyam","doi":"10.1016/j.gim.2026.102595","DOIUrl":"10.1016/j.gim.2026.102595","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to apply cardiometabolic genetic testing in a community setting with a predominantly Hispanic population and assess feasibility and perspectives toward genetic testing.</div></div><div><h3>Methods</h3><div>A genome-sequencing-based genetic panel for cardiometabolic disorders (177 genes related to monogenic conditions, 2 <em>LPA</em> risk alleles, 2 pharmacogenomic loci, and ancestry-adjusted polygenic risk scores for type 2 diabetes and coronary artery disease) was deployed in community cardiology and endocrinology clinics in South Texas. A survey on perceptions toward genetic testing was administered after return of results.</div></div><div><h3>Results</h3><div>Testing was completed for 776 patients (18-92 years old, 92% Hispanic). 26 patients (3.4%) were identified with a pathogenic or likely pathogenic variant in a monogenic disease gene, including 17 diagnostic and 9 secondary findings. Additionally, 291 (37.5%), 181 (23.3%), and 298 (38.4%) patients were identified with at least 1 <em>LPA</em> risk allele, pharmacogenomic finding, or elevated polygenic risk scores, respectively. Patients perceived the testing to be beneficial with few concerns.</div></div><div><h3>Conclusion</h3><div>This study expanded cardiometabolic genetic testing to a predominantly Hispanic population in a community setting, providing actionable guidance for disease diagnosis, intervention, and preventive care with a favorable patient perception.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 7","pages":"Article 102595"},"PeriodicalIF":6.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856160","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":"Detection of repeat expansion variants using next generation sequencing: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Saurav Guha,&nbsp;Indhu-Shree Rajan-Babu,&nbsp;Akanchha Kesari,&nbsp;Shreshtha Garg,&nbsp;Nancy C. Rose,&nbsp;Bryce A. Seifert,&nbsp;Honey V. Reddi,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2026.102520","DOIUrl":"10.1016/j.gim.2026.102520","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 7","pages":"Article 102520"},"PeriodicalIF":6.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251300","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":"Development of polyphenotypic scores to prioritize detection of G6PD rs1050828 heterozygotes in African and African American populations","authors":"Tianyuan Lu,&nbsp;David Stein,&nbsp;Wenmin Zhang,&nbsp;Yuval Itan,&nbsp;Andrew D. Paterson","doi":"10.1016/j.gim.2026.101943","DOIUrl":"10.1016/j.gim.2026.101943","url":null,"abstract":"<div><h3>Purpose</h3><div>The <em>G6PD</em> missense variant rs1050828 (NP_000393.4:p.Val98Met) is common in African and African American populations. It lowers HbA1c levels independent of glycemia, increasing the risk of underdiagnosis or delayed diagnosis of diabetes. We aimed to develop polyphenotypic scores (PPS) using routinely collected phenotypes to identify likely heteroygotes.</div></div><div><h3>Methods</h3><div>Using data from 31,083 African or African American participants in the All of Us Research Program, we developed sex-specific PPS through multistage variable selection. We validated the PPS in independent African or African American individuals from All of Us Research Program (<em>N</em> = 8846), BioMe Biobank (<em>N</em> = 8839), and UK Biobank (<em>N</em> = 6811) and evaluated their utility among individuals without diagnosed diabetes.</div></div><div><h3>Results</h3><div>The PPS achieved an area under the receiver operating characteristic curve ranging from 0.7614 to 0.8686 in identifying male hemizygotes and from 0.7378 to 0.8654 identifying female homozygotes. Among individuals without diagnosed diabetes and with HbA1c &lt; 6.5%, PPS-based screening reduced the number needed to screen for identifying male hemizygotes by 65% to 90% and female homozygotes by 80% to 90%, compared with random screening.</div></div><div><h3>Conclusion</h3><div>The PPS may help identify likely rs1050828 heterozygotes in African and African American populations, supporting prioritization for confirmatory testing or alternative diagnostic approaches for diabetes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 7","pages":"Article 101943"},"PeriodicalIF":6.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987343","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":"Clinical and genetic characterization of constitutional MLH1 promoter hypermethylation: Implications for Lynch syndrome diagnosis","authors":"Megan F.H. Bishop,&nbsp;Nisha Kanwar,&nbsp;Lauren E. Schefter,&nbsp;Richard G. Lahr,&nbsp;Jia W. Tan,&nbsp;Rhianna M. Urban,&nbsp;Megan A. Holdren,&nbsp;Carrie A. Lahner,&nbsp;Darcy J. Huismann,&nbsp;Mariam I. Stein,&nbsp;Jiayu Tan,&nbsp;Kandelaria M. Rumilla,&nbsp;Benjamin R. Kipp,&nbsp;Eric W. Klee,&nbsp;Stephen J. Murphy,&nbsp;Sounak Gupta,&nbsp;Wei Shen","doi":"10.1016/j.gim.2026.102594","DOIUrl":"10.1016/j.gim.2026.102594","url":null,"abstract":"<div><h3>Purpose</h3><div>Constitutional <em>MLH1</em> promoter hypermethylation (CMPH) is a relatively rare cause of Lynch syndrome. While most cases appear to be sporadic, some result from secondary epimutations, mainly caused by germline variants in the <em>MLH1</em> promoter region. This study describes the clinical phenotype and genetic etiology of CMPH in the largest clinical cohort to date.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted for 422 individuals who underwent clinical CMPH testing. Promoter sequencing was used to identify the underlying variants. Long-read sequencing further characterized <em>MLH1</em> promoter methylation.</div></div><div><h3>Results</h3><div>CMPH was identified in 15.6% of the study cohort participants. Of these, 63 exhibited clinical features consistent with Lynch syndrome. The most common associated cancers were colorectal cancer, followed by endometrial cancer, breast cancer, and sebaceous neoplasms. Mendelian inheritance of CMPH was observed in 5 families in the study cohort, indicating secondary epimutations. Promoter sequencing identified 8 unique germline variants, including 3 novel variants. Methylation analysis by long-read sequencing revealed mutant allele–specific promoter methylation for these variants.</div></div><div><h3>Conclusion</h3><div>Our findings provide the most comprehensive review of the clinical phenotype associated with CMPH and highlight the significant contribution of promoter variants to its etiology. These results underscore the need to include the assessment of constitutional <em>MLH1</em> promoter methylation for Lynch syndrome diagnosis.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 7","pages":"Article 102594"},"PeriodicalIF":6.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147928762","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}