Genetics in Medicine最新文献

{"title":"Common and Rare Genetic Variants Explain Distinct Diagnostic Variance in Pediatric Attention Deficit Hyperactivity Disorder.","authors":"Anne B Arnett, Ryan Koesterer, Paulina Gonzalez Tovar, Mia O'Connell, Soleha Patel, Han Zhang, Courtney E French, Shira Rockowitz, Jason Flannick, Ryan Doan","doi":"10.1016/j.gim.2025.101598","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101598","url":null,"abstract":"<p><strong>Purpose: </strong>Pediatric attention deficit hyperactivity disorder (ADHD, MIM: 143465) is highly heritable, yet the genetic architecture of the condition remains poorly understood. The current study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD.</p><p><strong>Methods: </strong>Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across five methods, including two published GWAS and two publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established ACMGG variant interpretation guidelines.</p><p><strong>Results: </strong>ADHD cases had higher ADHD polygenic scores and lower IQ polygenic scores. Likely pathogenic variants for ADHD were identified in 13% of cases and 0.5% of controls. ADHD polygenic scores among cases without rare variants were higher than cases carrying rare variants. ADHD cases were predicted by ADHD and IQ PGS, ancestry, and rare variant status with 70% area under the curve.</p><p><strong>Conclusions: </strong>The genetic etiology of ADHD is likely multifactorial, with independent contributions from common and rare variants. Genome wide association studies of ADHD may have increased power to detect common genetic loci if individuals with rare variants are excluded.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101598"},"PeriodicalIF":6.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274466","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":"Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)","authors":"Joanne Ngeow ,&nbsp;Jianbang Chiang ,&nbsp;Esteban Astiazaran-Symonds ,&nbsp;Judith Balmaña ,&nbsp;Ilana Cass ,&nbsp;Felix K.F. Kommoss ,&nbsp;William D. Foulkes ,&nbsp;Paul A. James ,&nbsp;Arielle Katcher ,&nbsp;Susan Klugman ,&nbsp;Alicia A. Livinski ,&nbsp;Julie S. Mak ,&nbsp;Nicoleta Voian ,&nbsp;Myra J. Wick ,&nbsp;Marc Tischkowitz ,&nbsp;Tuya Pal ,&nbsp;Douglas R. Stewart ,&nbsp;Helen Hanson ,&nbsp;ACMG Professional Practice and Guidelines Committee","doi":"10.1016/j.gim.2025.101557","DOIUrl":"10.1016/j.gim.2025.101557","url":null,"abstract":"<div><h3>Purpose</h3><div><em>RAD51C, RAD51D,</em> and <em>BRIP1</em> germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> heterozygotes in clinical practice are limited.</div></div><div><h3>Methods</h3><div>An international workgroup developed a Clinical Practice Resource to guide management of <em>RAD51C</em>, <em>RAD51D,</em> and <em>BRIP1</em> heterozygotes using peer-reviewed publications and expert opinion.</div></div><div><h3>Results</h3><div><em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> are moderate (intermediate) penetrance ovarian cancer predisposition genes. Ovarian cancer risks for individuals with <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> GPVs may be influenced by family history and other modifiers. <em>RAD51C</em> and <em>RAD51D</em> GPVs are also associated with moderate risk of breast cancer, predominantly triple-negative subtype. <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> heterozygotes should be offered risk-reducing salpingo-oophorectomy close to the age of menopause based on age-specific risks and shared decision making. For <em>RAD51C</em> and <em>RAD51D</em> heterozygotes, enhanced breast surveillance may be indicated according to their personalized risk estimate and country-specific guidelines. Generally, risk-reducing mastectomy is not recommended. For <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> heterozygotes who develop cancer, there is insufficient evidence to guide any specific targeted treatment.</div></div><div><h3>Conclusion</h3><div>Systematic prospective data collection is needed to establish the outcomes of <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> associated cancers and particularly response to cancer treatment and survival.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101557"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266880","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":"A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy.","authors":"Katharina Valentin, Monika Kustermann, Mona R Schneider, Haleh Aminfar, Kathrin Vollnhofer, Andreas Wedrich, Christoph Stapf, Martin Bertich, Markus Ritter, Theresa Mendrina, Daniel Valcanover, Walter Berger, Margret Eckhard, Andy Sombke, Stephanie V Lilja, Amina Paquay, Bernhard Rosensteiner, Iris Schmidt, Reginald E Bittner, Thomas P Georgi, Berthold Pemp, Wolfgang M Schmidt","doi":"10.1016/j.gim.2025.101595","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101595","url":null,"abstract":"<p><strong>Purpose: </strong>Hereditary optic atrophy (OA) represents one of the leading causes of blindness. A relatively large number of genes, many of which are implicated in mitochondrial function, are known to be involved in OA. For many affected individuals, however, a genetic cause still cannot be identified.</p><p><strong>Methods: </strong>In large pedigree and additional families, exome sequencing (ES) was used to identify a genetic cause in individuals with so far genetically unresolved OA. Subsequently, mitochondrial function was studied in cultured dermal fibroblasts.</p><p><strong>Results: </strong>ES revealed a heterozygous missense variant in PPIB [NM_000942.5:c.538C>T p.(Arg180Trp)], encoding peptidylprolyl isomerase B, which segregated with clinically isolated OA in 19 individuals from 9 families. PPIB-associated OA involves an insidious reduction in visual acuity, central scotoma and inner retinal layer thinning consistent with other autosomal dominant OAs. Age of symptom onset was mostly in adulthood (median: 36 years), and severity of clinical manifestation was variable. Patient-derived fibroblasts revealed altered mitochondrial morphology as well as subtle respiratory chain defects.</p><p><strong>Conclusions: </strong>The PPIB variant segregates with OA, which might be caused by compromised mitochondrial function. While future studies are needed to study the exact pathomechanistic role of PPIB, insights from this work broaden the knowledge of genes implicated in autosomal dominant OA.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101595"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225233","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":"Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure.","authors":"Erja Nynäs, Sonja Sulkava, Anna K Nurmi, Maija Suvanto, Kristiina Aittomäki, Heli Nevanlinna","doi":"10.1016/j.gim.2025.101521","DOIUrl":"10.1016/j.gim.2025.101521","url":null,"abstract":"<p><strong>Purpose: </strong>Heterozygous FANCM variants have been associated with breast cancer. Only a few studies have examined other cancer types. Biallelic truncating variants have been linked to a Fanconi anemia (FA)-like cancer prone syndrome in case reports; however, the range of cancers and the risk estimates are lacking.</p><p><strong>Methods: </strong>We studied the association of Finnish-enriched variants c.5101C>T p.(Gln1701Ter) and c.5791C>T p.(Arg1931Ter) with risk of any cancer and FA-related conditions in the FinnGen data with 500,348 individuals.</p><p><strong>Results: </strong>Heterozygous c.5101C>T (N = 10,940) was associated not only with an increased risk of breast cancer (odds ratio = 1.24, P = 2.7 × 10^-6) but also with risks of other cancer types, including hypopharyngeal (odds ratio = 3.98, P = 3.6 × 10^-7), suggesting a risk effect wider than previously described. Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer, whereas c.5791C>T was rare. Additionally, high recessive risks of ovarian dysfunction and hematologic side effects after cancer treatment were detected, but no risks of bone marrow failure or physical features of FA.</p><p><strong>Conclusion: </strong>Based on the pattern of risks associated with biallelic variants, we suggest a novel FANCM cancer syndrome that is separate from FA and other characterized cancer susceptibility syndromes.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101521"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608224","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":"Toward Ethical Provenance Tracking: The GA4GH Model Data Access Agreement (DAA).","authors":"Alexander Bernier, Bartha Maria Knoppers, Jonathan Lawson, Robyn McDougall, Maili Raven-Adams, Vasiliki Rahimzadeh","doi":"10.1016/j.gim.2025.101594","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101594","url":null,"abstract":"<p><strong>Purpose: </strong>Standardizing contractual clauses that govern data access enables research institutions to responsibly steward genomic and related health data while enabling its efficient downstream re-use.</p><p><strong>Methods: </strong>We describe a document analysis study using both qualitative and comparative law analytical approaches to identify the most common categories of clauses from 29 different data access agreements used by human biomedical research consortia globally. We furthermore characterized the legal positions and standard practices for each common element of the agreement and synthesized across them to develop model clauses. Three discussion sessions were organized virtually to refine the clauses among members of the Ethical Provenance Subgroup of the Global Alliance for Genomics and Health.</p><p><strong>Results: </strong>We developed 15 unique data access clauses corresponding to the most common legal elements identified in the sampled agreements.</p><p><strong>Conclusions: </strong>Model clauses can be used to drive administrative efficiencies and institutional compliance for managing access to human genomic data for research. Additional machine-readable consents and software solutions are needed to support traceable 'ethical provenance' of human genomic data and communicate data use conditions throughout data's life-cycle.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101594"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232428","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":"Real-world effects of using gnomAD 4.1.0 and AllofUs population reference datasets on reporting of variants of uncertain significance.","authors":"Runjun D Kumar, Sarah A Paolucci, Brittany Williams, Daniel W Serber, Claire L Wittowski, Ankita Jhuraney, Dru F Leistritz, Jillian G Buchan","doi":"10.1016/j.gim.2025.101593","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101593","url":null,"abstract":"<p><strong>Purpose: </strong>Clinical testing of rare genetic variants relies on population genomic datasets as a source of evidence. New datasets from the Genome Aggregation Database (gnomAD) and AllofUs Research Program are many-fold larger than prior datasets, and the latter includes highly detailed phenotype data. The effect of these datasets on variant classification and reporting for highly-penetrant pediatric-onset disease is not well characterized, but one likely effect is to reduce reporting of variants of uncertain significance (VUS).</p><p><strong>Methods: </strong>We retrospectively identified VUS previously reported by our CAP/CLIA certified laboratory and evaluated whether they are still reportable provided new reference datasets.</p><p><strong>Results: </strong>By examining allele counts in new datasets, we identified 24 variants that are likely no longer reportable. Additionally, the AllofUs phenotype data suggest an additional 10 VUS are no longer reportable. Overall, we find that nearly one fifth of VUS (34/173, 19.6%) are no longer reportable.</p><p><strong>Conclusion: </strong>We conclude that the use of these new datasets is likely to reduce reported VUS for highly-penetrant pediatric-onset disease. This may be further augmented through updated gene-specific thresholds and improved accessibility of AllofUs phenotype data.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101593"},"PeriodicalIF":6.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212300","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 Clinical Utility of Systematic Reporting of Secondary Findings in Prenatal Diagnosis.","authors":"Kaili Yin, Qingwei Qi, Xiya Zhou, Na Hao, Ru Wang, Jiazhen Chang, Mengmeng Li, Xueting Yang, Mingming Wang, Yan Lü, Yulin Jiang","doi":"10.1016/j.gim.2025.101596","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101596","url":null,"abstract":"<p><strong>Purpose: </strong>Secondary findings (SFs) identified through genomic sequencing are results unrelated to the primary indication but with potential clinical utility. While genomic technologies are increasingly utilized in perinatal diagnosis, the clinical implications of SFs remain insufficiently explored. We evaluated the detection rates, phenotypic concordance, and clinical implications of SFs in a prenatal cohort undergoing trio exome sequencing (trio-ES).</p><p><strong>Method: </strong>This was a single-center cohort study of 424 consecutive families who underwent prenatal trio-ES at a tertiary maternal-fetal medicine center from January 2019 to December 2023. SFs were classified using a three-category framework (medically actionable risks, childhood-onset diseases, carrier status) and analyzed via a stepwise protocol, including validation by a specialized clinical review panel.</p><p><strong>Results: </strong>Among 1,272 individuals, SFs were identified in 2.9% (37/1,272), including 2.1% of fetuses (9/424) and 3.3% of parents (28/848). SF-related phenotypes were observed in 1 fetus and 3 adults. SFs prompted medical management changes in 27.0% (10/37) of cases, including one pregnancy termination, seven adults initiating medical evaluations, and two couples committing to prenatal diagnosis/neonatal screening in subsequent pregnancies.</p><p><strong>Conclusions: </strong>Systematic SF reporting in prenatal diagnosis has demonstrated clinical value by facilitating pregnancy decisions, informing parental health risks, and enabling preventive reproductive strategies.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101596"},"PeriodicalIF":6.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225335","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":"Overcoming treatment implementation barriers for individuals with rare diseases using single-case experimental designs.","authors":"Annelieke R Müller, Bibiche den Hollander, Agnies M van Eeghen, Peter M van de Ven, Martina Cornel, Mieke van Haelst, Jan J Sprengers, Hilgo Bruining, Marion M Brands, Clara D van Karnebeek","doi":"10.1016/j.gim.2025.101592","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101592","url":null,"abstract":"<p><p>Treatments often do not reach individuals affected with a rare disease due to several barriers. Legislation generally requires that therapies for rare diseases are tested and licensed according to the same rules as established for common diseases. However, conventional methods for evaluating treatment effectiveness are hampered by the small patient populations. Single-case experimental designs (SCEDs), including n-of-1 trials, may offer a solution. Advantages of SCEDs include the ability to study individualized treatment options, use of within-participant randomization to generate a high level of evidence, and guaranteeing that each individual receives treatment. Their individualized approach also has a positive impact on ensuring relevance of treatment approaches and outcomes for affected individuals. However, designing and performing SCEDs in rare diseases comes with specific challenges related to heterogeneity, selection of outcome measures, accessibility of therapy, development of study medication, treatment and trial adherence, regulation, reimbursement, and financial limitations. Here the lessons learned from SCEDs in rare diseases are discussed, based on real-world experiences from the involved clinicians and researchers, and informal participants' comments collected during and after participation in a SCED. Following these experiences and a thorough evaluation by an expert group, a manual for conducting SCEDs has been developed. This manual is presented as a steppingstone towards robust evidence generation and better access to treatments for individuals with rare diseases.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101592"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206302","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":"HCSeeker: A Classification Tool for Human Genetic Variant Hot and Cold Spots Designed for PM1 and Benign Criteria in the ACMG-AMP Guideline.","authors":"Xinpan Yuan, Xingquan Xia, Jinchen Li, Guihu Zhao","doi":"10.1016/j.gim.2025.101591","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101591","url":null,"abstract":"<p><strong>Purpose: </strong>The PM1 criterion, which states that a variant is located in a mutational hot spot and/or critical and well-established functional domain without benign variation (such as the active site of an enzyme), is considered moderate evidence for assessing its pathogenicity. Although guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) are widely adopted, the PM1 criterion remains limited from lacking a reliable database of variant hot spots. Compared to hot spots, cold spots are neglected by the guidelines. To improve variant classification, we suggest including cold spots for supporting benign classifications. Consequently , we have developed the HCSeeker to provide data support for PM1 and the 'Benign' criteria.</p><p><strong>Methods: </strong>HCSeeker employs the Kernel Density Estimation (KDE) and the Expectation-Maximization (EM) algorithm to identify hot and cold spot regions.</p><p><strong>Results: </strong>Through HCSeeker, we identified 988 hot spots and 682 cold spots across 889 genes and provided a public database (http://www.genemed.tech/hcseeker/) for researchers and clinicians to query variant locations, facilitating the application of ACMG/AMP PM1 or 'Benign' criteria.</p><p><strong>Conclusion: </strong>We developed the HCSeeker tool, which can effectively identify variant hot and cold spots within genes to enhancing the interpretability of gene variants.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101591"},"PeriodicalIF":6.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185663","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":"Infantile-onset Pompe disease entering adulthood: insights from two decades of enzyme replacement therapy experience.","authors":"Neha Regmi, Daniel Kenney-Jung, Grace Stafford, Michael Malinzak, Gail A Spiridigliozzi, Tracy Boggs, Rebecca L Koch, Phillip Brian Smith, Laura E Case, Sarah P Young, Harrison N Jones, Priya S Kishnani","doi":"10.1016/j.gim.2025.101590","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101590","url":null,"abstract":"<p><strong>Purpose: </strong>This study details the long-term clinical outcomes in adult participants with CRIM-positive infantile-onset Pompe disease (IOPD) treated with enzyme replacement therapy (ERT), initially reported in 2012 (n=11).</p><p><strong>Methods: </strong>Medical records were reviewed for multisystem involvement and biomarker trends. Central nervous system (CNS) involvement was evaluated using a Modified Fazekas Score (MFS) to grade white matter hyperintensities (WMHI) on brain MRI.</p><p><strong>Results: </strong>Of the initial 11 participants, 8 survived to adulthood (median age 19.6 years); 3 died (2 of arrhythmia, 1 of status epilepticus). All survivors began ERT between 0.2-6 months of age (seven at 20 mg/kg biweekly; one at 40 mg/kg biweekly), with subsequent escalation to 40 mg/kg/week of alglucosidase alfa between ages 8-15 years. None received immune modulation. Cardiac hypertrophy resolved in all; two developed arrhythmias requiring intervention. None required invasive ventilation. Two participants were ambulatory, six used wheelchairs. Flaccid dysarthria (8/8), ptosis (4/8), and sensorineural hearing loss (6/8) were common. WMHI were present in all but remained mild to moderate on MFS. Cognitive function remained stable.</p><p><strong>Conclusions: </strong>Long-term ERT preserves cardiac and respiratory function in adult IOPD survivors, but multisystem morbidity persists, highlighting the need for earlier diagnosis and better therapies targeting muscle and other tissues including the CNS.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101590"},"PeriodicalIF":6.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174726","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}