Pub Date : 2026-01-01Epub Date: 2025-10-14DOI: 10.1016/j.gim.2025.101613
Vanessa C. Jacovas , Michelle Zelnick , Shannon McNulty , Justyne E. Ross , Namrata Khurana , Xueyang Pan , Alejandro Nieto , Shiloh Martin , Benjamin McLean , Marwa A. Elnagheeb , Morton J. Cowan , Jennifer M. Puck , Mike S. Hershfield , James Verbsky , Jolan Walter , Eric J. Allenspach , Alice Y. Chan , Nicolai S.C. van Oers , Rajarshi Ghosh , Megan Piazza , Xinrui Shi
Purpose
This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2.
Methods
The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These specifications were validated using a pilot set of 90 variants.
Results
Of these 90 variants, 25 were classified as pathogenic, 21 as likely pathogenic, 14 as variants of uncertain significance, 18 as likely benign, and 12 as benign. Seventeen variants with conflicting classifications in ClinVar were successfully resolved. The criteria included modifications to 20 of the 28 original ACMG/AMP criteria specific to SCID-related genes.
Conclusion
The SCID-specific variant curation guidelines developed by the SCID-VCEP will enhance the precision of SCID genetic diagnosis and provide a robust framework for interpreting variants in SCID-related genes, contributing to appropriate treatment of SCID.
{"title":"The ClinGen Severe Combined Immunodeficiency Disease Variant Curation Expert Panel: Specifications for classification of variants in ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2","authors":"Vanessa C. Jacovas , Michelle Zelnick , Shannon McNulty , Justyne E. Ross , Namrata Khurana , Xueyang Pan , Alejandro Nieto , Shiloh Martin , Benjamin McLean , Marwa A. Elnagheeb , Morton J. Cowan , Jennifer M. Puck , Mike S. Hershfield , James Verbsky , Jolan Walter , Eric J. Allenspach , Alice Y. Chan , Nicolai S.C. van Oers , Rajarshi Ghosh , Megan Piazza , Xinrui Shi","doi":"10.1016/j.gim.2025.101613","DOIUrl":"10.1016/j.gim.2025.101613","url":null,"abstract":"<div><h3>Purpose</h3><div>This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: <em>ADA</em>, <em>DCLRE1C</em>, <em>IL2RG</em>, <em>IL7R</em>, <em>JAK3</em>, <em>RAG1</em>, and <em>RAG2</em>.</div></div><div><h3>Methods</h3><div>The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These specifications were validated using a pilot set of 90 variants.</div></div><div><h3>Results</h3><div>Of these 90 variants, 25 were classified as pathogenic, 21 as likely pathogenic, 14 as variants of uncertain significance, 18 as likely benign, and 12 as benign. Seventeen variants with conflicting classifications in ClinVar were successfully resolved. The criteria included modifications to 20 of the 28 original ACMG/AMP criteria specific to SCID-related genes.</div></div><div><h3>Conclusion</h3><div>The SCID-specific variant curation guidelines developed by the SCID-VCEP will enhance the precision of SCID genetic diagnosis and provide a robust framework for interpreting variants in SCID-related genes, contributing to appropriate treatment of SCID.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101613"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307533","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}
Pub Date : 2026-01-01Epub Date: 2025-11-04DOI: 10.1016/j.gim.2025.101631
Aantaki Raisa , Irania Santaliz Moreno , Amy Ayala , Jada G. Hamilton , Jessica Mozersky , Erin Linnenbringer , Julia Maki , Amy McQueen , George P. Souroullas , Erika A. Waters
Purpose
This study aimed to explore how health-related epigenetic concepts are depicted in YouTube videos, a widely accessed platform for informal science education. As epigenetics becomes increasingly relevant to medical therapeutics, it is essential to understand what information is being disseminated in the public sphere.
Methods
We conducted a content analysis of 296 YouTube videos about epigenetics that were under 10 minutes in length. We transcribed and analyzed the videos using an iteratively developed codebook and then categorized relevant codes as categories.
Results
We identified 7 categories: (1) defining epigenetics, (2) causes of epigenetic changes, (3) effects of epigenetic change, (4) epigenetic inheritability, (5) application of epigenetics, (6) personal control, and (7) epigenetic mysticism. Although the content about the molecular epigenetic mechanisms mostly aligned with the latest scientific findings, there were numerous unsubstantiated and exaggerated claims about effects of epigenetics on human health, especially disease outcomes.
Conclusion
We identified several scientific concepts described on YouTube regarding epigenetics. Our findings also reveal what information about epigenetics is widely shared in the public sphere, helping to identify key misconceptions to address and guiding the development of strategies for accurate scientific communication.
{"title":"A content analysis of health-related epigenetic information in YouTube videos","authors":"Aantaki Raisa , Irania Santaliz Moreno , Amy Ayala , Jada G. Hamilton , Jessica Mozersky , Erin Linnenbringer , Julia Maki , Amy McQueen , George P. Souroullas , Erika A. Waters","doi":"10.1016/j.gim.2025.101631","DOIUrl":"10.1016/j.gim.2025.101631","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to explore how health-related epigenetic concepts are depicted in YouTube videos, a widely accessed platform for informal science education. As epigenetics becomes increasingly relevant to medical therapeutics, it is essential to understand what information is being disseminated in the public sphere.</div></div><div><h3>Methods</h3><div>We conducted a content analysis of 296 YouTube videos about epigenetics that were under 10 minutes in length. We transcribed and analyzed the videos using an iteratively developed codebook and then categorized relevant codes as categories.</div></div><div><h3>Results</h3><div>We identified 7 categories: (1) defining epigenetics, (2) causes of epigenetic changes, (3) effects of epigenetic change, (4) epigenetic inheritability, (5) application of epigenetics, (6) personal control, and (7) epigenetic mysticism. Although the content about the molecular epigenetic mechanisms mostly aligned with the latest scientific findings, there were numerous unsubstantiated and exaggerated claims about effects of epigenetics on human health, especially disease outcomes.</div></div><div><h3>Conclusion</h3><div>We identified several scientific concepts described on YouTube regarding epigenetics. Our findings also reveal what information about epigenetics is widely shared in the public sphere, helping to identify key misconceptions to address and guiding the development of strategies for accurate scientific communication.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101631"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470881","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}
Pub Date : 2026-01-01Epub Date: 2026-01-06DOI: 10.1016/j.gim.2025.101638
Sally L. Sansom , Chloe Mighton , Hadley Stevens Smith
{"title":"Correspondence on “Parents’ perceptions of the utility of genetic testing in the NICU” by Callahan et al","authors":"Sally L. Sansom , Chloe Mighton , Hadley Stevens Smith","doi":"10.1016/j.gim.2025.101638","DOIUrl":"10.1016/j.gim.2025.101638","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101638"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932874","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}
Pub Date : 2026-01-01Epub Date: 2026-01-06DOI: 10.1016/j.gim.2025.101628
Sonja A. Rasmussen, Ada Hamosh
{"title":"Response to Zlotogora","authors":"Sonja A. Rasmussen, Ada Hamosh","doi":"10.1016/j.gim.2025.101628","DOIUrl":"10.1016/j.gim.2025.101628","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101628"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932991","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}
Pub Date : 2026-01-01Epub Date: 2025-10-24DOI: 10.1016/j.gim.2025.101620
Thiloka Ratnaike , Siddharth Ramanan , Nour Elkhateeb , Ramya Narayanan , Jenny Yang , Eszter Sara Arany , Manya Mirchandani , Rachael Piper , Katherine Schon , M. Eren Kule , Christopher Gilmartin , Angela Lochmüller , Emogene Shaw , Rita Horváth , Patrick F. Chinnery
Purpose
Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
Methods
Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
Results
MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
Conclusion
MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.
{"title":"Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants","authors":"Thiloka Ratnaike , Siddharth Ramanan , Nour Elkhateeb , Ramya Narayanan , Jenny Yang , Eszter Sara Arany , Manya Mirchandani , Rachael Piper , Katherine Schon , M. Eren Kule , Christopher Gilmartin , Angela Lochmüller , Emogene Shaw , Rita Horváth , Patrick F. Chinnery","doi":"10.1016/j.gim.2025.101620","DOIUrl":"10.1016/j.gim.2025.101620","url":null,"abstract":"<div><h3>Purpose</h3><div>Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the <em>MitoPhen</em> database to characterize phenotypic variation across PMD more systematically.</div></div><div><h3>Methods</h3><div>Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce <em>MitoPhen v2</em>. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.</div></div><div><h3>Results</h3><div><em>MitoPhen v2</em> adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using <em>MT-TL1</em>, single large-scale mitochondrial DNA deletions, and <em>POLG</em> as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.</div></div><div><h3>Conclusion</h3><div><em>MitoPhen v2</em> enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101620"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577362","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}
Pub Date : 2026-01-01Epub Date: 2025-10-11DOI: 10.1016/j.gim.2025.101597
David Cheerie , Marlen C. Lauffer , Logan Newton , Kimberly Amburgey , Danique Beijer , Bushra Haque , Brian T. Kalish , Margaret M. Meserve , Rachel Y. Oh , Amy Y. Pan , Miriam S. Reuter , Michael J. Szego , Anna Szuto
Purpose
To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment.
Methods
We retrospectively applied the N=1 Collaborative’s Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either “eligible,” “likely eligible,” “unlikely eligible,” or “not eligible” in relation to the different ASO approaches, or “unable to assess.”
Results
In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development.
Conclusion
A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.
{"title":"Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study","authors":"David Cheerie , Marlen C. Lauffer , Logan Newton , Kimberly Amburgey , Danique Beijer , Bushra Haque , Brian T. Kalish , Margaret M. Meserve , Rachel Y. Oh , Amy Y. Pan , Miriam S. Reuter , Michael J. Szego , Anna Szuto","doi":"10.1016/j.gim.2025.101597","DOIUrl":"10.1016/j.gim.2025.101597","url":null,"abstract":"<div><h3>Purpose</h3><div>To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment.</div></div><div><h3>Methods</h3><div>We retrospectively applied the N=1 Collaborative’s Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either “eligible,” “likely eligible,” “unlikely eligible,” or “not eligible” in relation to the different ASO approaches, or “unable to assess.”</div></div><div><h3>Results</h3><div>In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development.</div></div><div><h3>Conclusion</h3><div>A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101597"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291915","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}
Pub Date : 2025-12-18DOI: 10.1016/j.gim.2025.101669
Shawn E McCandless
{"title":"Timeliness of reporting NBS results for Krabbe disease.","authors":"Shawn E McCandless","doi":"10.1016/j.gim.2025.101669","DOIUrl":"10.1016/j.gim.2025.101669","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101669"},"PeriodicalIF":6.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804380","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}
Pub Date : 2025-12-18DOI: 10.1016/j.gim.2025.101664
Mei Deng , Cheng Liu , Fang Shen , Yu Zheng , Zhenqing Luo , Hua Wang , Guanghui Zhu , Yongjia Yang
Purpose
Although radioulnar synostosis (RUS) and other skeletal anomalies are features of the 8q22.2q22.3 microdeletion syndrome, the precise genetic etiology of RUS remains undefined. Here, we aimed to definethe genetic basis of joint fusion in this syndrome.
Methods
We performed combined chromosomal microarray (CMA), high-throughput ligation-dependent probe amplification (HLPA), and exome sequencing (ES) on RUS probands and families. Variant effects were assessed through structural modeling, Western blot, and immunofluorescence. Murine Osr2 knockout phenotypes were evaluated via literature review.
Results
A 383.28-kb heterozygous deletion at 8q22.2 (arr[GRCh37] 8q22.2(99903192_100286471)x1), completely encompassing OSR2 (HGNC:15830), was identified in a mother-son pair with RUS. ES revealed OSR2 variants in five unrelated pedigrees: the nonsense variant c.481C>T p.(Arg161Ter) in two families, c.174T>A p.(Tyr58Ter) in one family, and two missense variants (c.628C>T p.(Arg210Trp) and c.628C>G p.(Arg210Gly), each in one family. Clinical reevaluation identified additional phenotypes, including distal ulna hypoplasia, joint stiffness, ear deformity, scoliosis, and short stature in individuals harboring OSR2 variants. Functional studies demonstrated loss-of-function mechanisms (absent/truncated protein or impaired nuclear localization). Literature showed Osr2 knockout mice phenocopied human joint fusion.
Conclusion
This study links OSR2 haploinsufficiency or loss-of-function variants to RUS and other skeletal malformations.
{"title":"Heterozygous Loss of OSR2 Can Cause Radio-Ulnar Synostosis with Ancillary Skeletal Manifestations","authors":"Mei Deng , Cheng Liu , Fang Shen , Yu Zheng , Zhenqing Luo , Hua Wang , Guanghui Zhu , Yongjia Yang","doi":"10.1016/j.gim.2025.101664","DOIUrl":"10.1016/j.gim.2025.101664","url":null,"abstract":"<div><h3>Purpose</h3><div>Although radioulnar synostosis (RUS) and other skeletal anomalies are features of the 8q22.2q22.3 microdeletion syndrome, the precise genetic etiology of RUS remains undefined. Here, we aimed to definethe genetic basis of joint fusion in this syndrome.</div></div><div><h3>Methods</h3><div>We performed combined chromosomal microarray (CMA), high-throughput ligation-dependent probe amplification (HLPA), and exome sequencing (ES) on RUS probands and families. Variant effects were assessed through structural modeling, Western blot, and immunofluorescence. Murine <em>Osr2</em> knockout phenotypes were evaluated via literature review.</div></div><div><h3>Results</h3><div>A 383.28-kb heterozygous deletion at 8q22.2 (arr[GRCh37] 8q22.2(99903192_100286471)x1), completely encompassing <em>OSR2</em> (HGNC:15830), was identified in a mother-son pair with RUS. ES revealed <em>OSR2</em> variants in five unrelated pedigrees: the nonsense variant c.481C>T p.(Arg161Ter) in two families, c.174T>A p.(Tyr58Ter) in one family, and two missense variants (c.628C>T p.(Arg210Trp) and c.628C>G p.(Arg210Gly), each in one family. Clinical reevaluation identified additional phenotypes, including distal ulna hypoplasia, joint stiffness, ear deformity, scoliosis, and short stature in individuals harboring <em>OSR2</em> variants. Functional studies demonstrated loss-of-function mechanisms (absent/truncated protein or impaired nuclear localization). Literature showed <em>Osr2</em> knockout mice phenocopied human joint fusion.</div></div><div><h3>Conclusion</h3><div>This study links <em>OSR2</em> haploinsufficiency or loss-of-function variants to RUS and other skeletal malformations.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101664"},"PeriodicalIF":6.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804356","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}
Pub Date : 2025-12-01Epub Date: 2025-09-23DOI: 10.1016/j.gim.2025.101590
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
Purpose
This study details the long-term clinical outcomes in adult participants with CRIM-positive infantile-onset Pompe disease treated with enzyme replacement therapy (ERT), initially reported in 2012 (n = 11).
Methods
Medical records were reviewed for multisystem involvement and biomarker trends. Central nervous system involvement was evaluated using a Modified Fazekas Score to grade white matter hyperintensities on brain magnetic resonance imaging.
Results
Of the initial 11 participants, 8 had survived to adulthood (median age 19.6 years), and 3 died (2 of arrhythmia, 1 of status epilepticus). All survivors began ERT between 0.2 to 6 months of age (7 at 20 mg/kg biweekly; 1 at 40 mg/kg biweekly), with subsequent escalation to 40 mg/kg/week of alglucosidase alfa between ages 8 to 15 years. None of the participants received immune modulation. Cardiac hypertrophy was resolved in all; 2 developed arrhythmias requiring intervention. None of the participants required invasive ventilation. Two participants were ambulatory; 6 used wheelchairs. Flaccid dysarthria (8/8), ptosis (4/8), and sensorineural hearing loss (6/8) were common. White matter hyperintensities were present in all but remained mild to moderate on Modified Fazekas Score. Cognitive function remained stable.
Conclusion
Long-term ERT preserves cardiac and respiratory function in adult infantile-onset Pompe disease survivors; however, multisystem morbidity persists, highlighting the need for earlier diagnosis and better therapies targeting muscle and other tissues including the central nervous system.
{"title":"Infantile-onset Pompe disease entering adulthood: Insights from 2 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":"10.1016/j.gim.2025.101590","url":null,"abstract":"<div><h3>Purpose</h3><div>This study details the long-term clinical outcomes in adult participants with CRIM-positive infantile-onset Pompe disease treated with enzyme replacement therapy (ERT), initially reported in 2012 (<em>n</em> = 11).</div></div><div><h3>Methods</h3><div>Medical records were reviewed for multisystem involvement and biomarker trends. Central nervous system involvement was evaluated using a Modified Fazekas Score to grade white matter hyperintensities on brain magnetic resonance imaging.</div></div><div><h3>Results</h3><div>Of the initial 11 participants, 8 had survived to adulthood (median age 19.6 years), and 3 died (2 of arrhythmia, 1 of status epilepticus). All survivors began ERT between 0.2 to 6 months of age (7 at 20 mg/kg biweekly; 1 at 40 mg/kg biweekly), with subsequent escalation to 40 mg/kg/week of alglucosidase alfa between ages 8 to 15 years. None of the participants received immune modulation. Cardiac hypertrophy was resolved in all; 2 developed arrhythmias requiring intervention. None of the participants required invasive ventilation. Two participants were ambulatory; 6 used wheelchairs. Flaccid dysarthria (8/8), ptosis (4/8), and sensorineural hearing loss (6/8) were common. White matter hyperintensities were present in all but remained mild to moderate on Modified Fazekas Score. Cognitive function remained stable.</div></div><div><h3>Conclusion</h3><div>Long-term ERT preserves cardiac and respiratory function in adult infantile-onset Pompe disease survivors; however, multisystem morbidity persists, highlighting the need for earlier diagnosis and better therapies targeting muscle and other tissues including the central nervous system.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101590"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","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}
Pub Date : 2025-12-01Epub Date: 2025-04-19DOI: 10.1016/j.gim.2025.101446
Bethany Stafford-Smith , Morgan Daniel , Michelle Peter , Jana Gurasashvili , Rashida Baptiste , Xavier Bracke-Manzanares , Lamprini Georgiou , Adele Green-Armytage , Blanche Griffin , Bethany Lumborg , Ben Paternoster , Emma Smith , Meena Balasubramanian , Lucy Bownass , Paul Brennan , Ruth Cleaver , Virginia Clowes , Philandra Costello , Bianca DeSouza , Louise Dubois , Melissa Hill
Purpose
The 100,000 Genomes Project participants could consent to receive additional findings (AFs) for variants associated with susceptibility to cancer and familial hypercholesterolemia. Here, we evaluate stakeholder experiences to inform clinical practice.
Methods
Mixed-methods study conducted at 18 sites across England that comprised a cross-sectional survey and interviews with participants who received a positive AF (PAF) and interviews with participants who had no AFs (NAF).
Results
There were 146 surveys followed by 35 interviews with PAF participants and 29 interviews with NAF participants. Surveys found that PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members. Experiences differed by PAF type; cancer PAF participants were often initially shocked and anxious and found telling family members challenging compared with participants with a familial hypercholesterolemia PAF. Although most experiences of NAF results were positive, some misunderstandings were identified. Participants supported returning AFs when offering genome sequencing.
Conclusion
Patient experiences of receiving AFs were primarily positive, and there is support for offering AFs routinely. Considerations for offering AFs in clinical practice include adapting approaches tailored to individual conditions and greater support for people with a NAF result.
{"title":"Evaluating the return of additional findings from the 100,000 Genomes Project: A mixed-methods study exploring participant experiences of receiving secondary findings from genomic sequencing","authors":"Bethany Stafford-Smith , Morgan Daniel , Michelle Peter , Jana Gurasashvili , Rashida Baptiste , Xavier Bracke-Manzanares , Lamprini Georgiou , Adele Green-Armytage , Blanche Griffin , Bethany Lumborg , Ben Paternoster , Emma Smith , Meena Balasubramanian , Lucy Bownass , Paul Brennan , Ruth Cleaver , Virginia Clowes , Philandra Costello , Bianca DeSouza , Louise Dubois , Melissa Hill","doi":"10.1016/j.gim.2025.101446","DOIUrl":"10.1016/j.gim.2025.101446","url":null,"abstract":"<div><h3>Purpose</h3><div>The 100,000 Genomes Project participants could consent to receive additional findings (AFs) for variants associated with susceptibility to cancer and familial hypercholesterolemia. Here, we evaluate stakeholder experiences to inform clinical practice.</div></div><div><h3>Methods</h3><div>Mixed-methods study conducted at 18 sites across England that comprised a cross-sectional survey and interviews with participants who received a positive AF (PAF) and interviews with participants who had no AFs (NAF).</div></div><div><h3>Results</h3><div>There were 146 surveys followed by 35 interviews with PAF participants and 29 interviews with NAF participants. Surveys found that PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members. Experiences differed by PAF type; cancer PAF participants were often initially shocked and anxious and found telling family members challenging compared with participants with a familial hypercholesterolemia PAF. Although most experiences of NAF results were positive, some misunderstandings were identified. Participants supported returning AFs when offering genome sequencing.</div></div><div><h3>Conclusion</h3><div>Patient experiences of receiving AFs were primarily positive, and there is support for offering AFs routinely. Considerations for offering AFs in clinical practice include adapting approaches tailored to individual conditions and greater support for people with a NAF result.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101446"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013679","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号