Pub Date : 2026-01-01DOI: 10.1016/j.gim.2025.101619
Emma Wakeling , Rashida Baptiste , Clarissa Rocca , Bethan Hoskins , Christopher Clarkson , Lyn S. Chitty , Arianna Tucci
Purpose
Genome sequencing (GS) is increasingly used to investigate rare conditions, primarily in children. The 100,000 Genomes Project (100KG) evaluated GS ahead of implementation in the English National Health Service. In 2020, the National Health Service Genomic Medicine Service (GMS) became the first public health care system to offer GS in routine clinical care. We investigate how learning from 100KG informed GMS service delivery.
Methods
We compare GS outcomes in children tested at a large pediatric hospital via GMS (n = 501) and 100KG research (n = 1759).
Results
GMS diagnostic yield (29%) was higher than that in 100KG (22%) (P < .0016). Median age at testing was 8 years in 100KG and 6 in the GMS (P < .05). In 100KG, the diagnostic yield was <10% for 15 indications, none of which are included in GMS testing. 100KG data showed little benefit to application of >3 panels. Use of fewer but larger GMS panels resulted in a significantly higher number of genes tested per patient: median 2801 vs 1373 in 100KG (P < .001). In 100KG, diagnostic yield was not significantly increased by testing more than 3 family members (n = 34/142, 24%).
Conclusion
Learning from 100KG has informed GS clinical service delivery, resulting in higher diagnostic yields and earlier age at testing. Lessons are broadly applicable to all services providing GS, enabling earlier access to tailored management with fewer investigations.
{"title":"Delivering effective genome sequencing in pediatric care: From research in the 100,000 Genomes Project to routine clinical practice","authors":"Emma Wakeling , Rashida Baptiste , Clarissa Rocca , Bethan Hoskins , Christopher Clarkson , Lyn S. Chitty , Arianna Tucci","doi":"10.1016/j.gim.2025.101619","DOIUrl":"10.1016/j.gim.2025.101619","url":null,"abstract":"<div><h3>Purpose</h3><div>Genome sequencing (GS) is increasingly used to investigate rare conditions, primarily in children. The 100,000 Genomes Project (100KG) evaluated GS ahead of implementation in the English National Health Service. In 2020, the National Health Service Genomic Medicine Service (GMS) became the first public health care system to offer GS in routine clinical care. We investigate how learning from 100KG informed GMS service delivery.</div></div><div><h3>Methods</h3><div>We compare GS outcomes in children tested at a large pediatric hospital via GMS (<em>n</em> = 501) and 100KG research (<em>n</em> = 1759).</div></div><div><h3>Results</h3><div>GMS diagnostic yield (29%) was higher than that in 100KG (22%) (<em>P</em> < .0016). Median age at testing was 8 years in 100KG and 6 in the GMS (<em>P</em> < .05). In 100KG, the diagnostic yield was <10% for 15 indications, none of which are included in GMS testing. 100KG data showed little benefit to application of >3 panels. Use of fewer but larger GMS panels resulted in a significantly higher number of genes tested per patient: median 2801 vs 1373 in 100KG (<em>P</em> < .001). In 100KG, diagnostic yield was not significantly increased by testing more than 3 family members (<em>n</em> = 34/142, 24%).</div></div><div><h3>Conclusion</h3><div>Learning from 100KG has informed GS clinical service delivery, resulting in higher diagnostic yields and earlier age at testing. Lessons are broadly applicable to all services providing GS, enabling earlier access to tailored management with fewer investigations.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101619"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654168","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 : 2026-01-01DOI: 10.1016/j.gim.2025.101636
Daffodil M. Canson , George A.R. Wiggins , Logan C. Walker , Amanda B. Spurdle
{"title":"Correspondence on “Genome sequencing reveals the impact of pseudoexons in rare genetic disease” by Pitsava et al","authors":"Daffodil M. Canson , George A.R. Wiggins , Logan C. Walker , Amanda B. Spurdle","doi":"10.1016/j.gim.2025.101636","DOIUrl":"10.1016/j.gim.2025.101636","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101636"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932950","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 : 2026-01-01DOI: 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 : 2026-01-01DOI: 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 : 2025-12-22DOI: 10.1016/j.gim.2025.101666
Jessica Rosenblum, Ellen Rijckmans, Randy Osei, Katrien Janssens, Ligia Mateiu, Catharina Olsen, Katrien Stouffs, Marije Meuwissen, Anna C Jansen
Purpose: Transcriptomics by way of RNA sequencing (RNAseq) has emerged as a means to increase the diagnostic yield in genetic conditions. In this systematic review, we focus on the contribution of transcriptomics to improve the diagnostic yield in neurodevelopmental disorders.
Methods: We performed a systematic literature search in PubMed until January 2024, including articles describing diagnostic RNAseq on at least one individual with a primary neurodevelopmental phenotype. We extracted data on cohort size, phenotype, sample tissue, previously used diagnostic methods, added diagnostic yield of RNAseq, the use of control samples, and technical aspects of the RNA sequencing methodology.
Results: 17 articles were eligible for inclusion in the systematic review. We found an average added diagnostic yield of 15·5% through RNA sequencing for individuals with neurodevelopmental disorders. There is heterogeneity in the tissue type, reported quality measures, and the computational pipeline.
Conclusion: The significantly increased diagnostic yield demonstrates the value of this novel tool in the diagnostic setting of neurodevelopmental disorders. Our results offer an overview of common methodologies for RNAseq and allow us to formulate recommendations for genetic labs and clinicians when implementing RNAseq as a diagnostic tool. Lastly, we provide recommendations for future publications in order to increase transparency and reproducibility.
{"title":"RNA sequencing offers new diagnostic opportunities in neurodevelopmental disorders: a systematic review.","authors":"Jessica Rosenblum, Ellen Rijckmans, Randy Osei, Katrien Janssens, Ligia Mateiu, Catharina Olsen, Katrien Stouffs, Marije Meuwissen, Anna C Jansen","doi":"10.1016/j.gim.2025.101666","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101666","url":null,"abstract":"<p><strong>Purpose: </strong>Transcriptomics by way of RNA sequencing (RNAseq) has emerged as a means to increase the diagnostic yield in genetic conditions. In this systematic review, we focus on the contribution of transcriptomics to improve the diagnostic yield in neurodevelopmental disorders.</p><p><strong>Methods: </strong>We performed a systematic literature search in PubMed until January 2024, including articles describing diagnostic RNAseq on at least one individual with a primary neurodevelopmental phenotype. We extracted data on cohort size, phenotype, sample tissue, previously used diagnostic methods, added diagnostic yield of RNAseq, the use of control samples, and technical aspects of the RNA sequencing methodology.</p><p><strong>Results: </strong>17 articles were eligible for inclusion in the systematic review. We found an average added diagnostic yield of 15·5% through RNA sequencing for individuals with neurodevelopmental disorders. There is heterogeneity in the tissue type, reported quality measures, and the computational pipeline.</p><p><strong>Conclusion: </strong>The significantly increased diagnostic yield demonstrates the value of this novel tool in the diagnostic setting of neurodevelopmental disorders. Our results offer an overview of common methodologies for RNAseq and allow us to formulate recommendations for genetic labs and clinicians when implementing RNAseq as a diagnostic tool. Lastly, we provide recommendations for future publications in order to increase transparency and reproducibility.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101666"},"PeriodicalIF":6.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827571","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 : 2025-12-19DOI: 10.1016/j.gim.2025.101670
Anna Luiza Braga Albuquerque , Maria Inez Dacoregio , Cainã Gonçalves Rodrigues , Débora Romeo Bertola , Paulo Victor Zattar Ribeiro
Purpose
Achondroplasia is the most common skeletal dysplasia, caused by gain-of-function variants in FGFR3, resulting in constitutive receptor activation and downstream inhibition of endochondral ossification. In 2021, the first targeted therapy, vosoritide, was approved in some countries after a landmark randomized trial. Although findings are promising, evidence is limited to modest-sized cohorts. To address this, we conducted a systematic review and meta-analysis of available vosoritide data.
Methods
A systematic search of PubMed, Cochrane, and Embase was conducted. Data were extracted according to Cochrane guidelines. Outcomes consistently reported were synthesized using R (v4.5) to generate forest plots.
Results
Ten studies were analyzed, encompassing 696 pediatric patients. Meta-analysis of single means showed that height z-score variation after 12 months of treatment was 0.32 (95% CI 0.25-0.40), annualized growth rate was 1.82 cm/year higher after treatment (95% CI 1.46-2.18), and the ratio between sitting height and height showed −0.0089 decrease (95% CI −0.0157 to −0.0020). Studies reported uniform profiles of adverse events, mostly limited to mild injection-site related issues and no serious complications.
Conclusion
This meta-analysis shows that real-world observational data on vosoritide in children with achondroplasia replicate clinical trial findings, with greater gains in linear growth and a similarly favorable safety profile.
{"title":"Real-world outcomes of vosoritide in achondroplasia: A systematic review and meta-analysis of multinational clinical evidence","authors":"Anna Luiza Braga Albuquerque , Maria Inez Dacoregio , Cainã Gonçalves Rodrigues , Débora Romeo Bertola , Paulo Victor Zattar Ribeiro","doi":"10.1016/j.gim.2025.101670","DOIUrl":"10.1016/j.gim.2025.101670","url":null,"abstract":"<div><h3>Purpose</h3><div>Achondroplasia is the most common skeletal dysplasia, caused by gain-of-function variants in <em>FGFR3</em>, resulting in constitutive receptor activation and downstream inhibition of endochondral ossification. In 2021, the first targeted therapy, vosoritide, was approved in some countries after a landmark randomized trial. Although findings are promising, evidence is limited to modest-sized cohorts. To address this, we conducted a systematic review and meta-analysis of available vosoritide data.</div></div><div><h3>Methods</h3><div>A systematic search of PubMed, Cochrane, and Embase was conducted. Data were extracted according to Cochrane guidelines. Outcomes consistently reported were synthesized using R (v4.5) to generate forest plots.</div></div><div><h3>Results</h3><div>Ten studies were analyzed, encompassing 696 pediatric patients. Meta-analysis of single means showed that height <em>z</em>-score variation after 12 months of treatment was 0.32 (95% CI 0.25-0.40), annualized growth rate was 1.82 cm/year higher after treatment (95% CI 1.46-2.18), and the ratio between sitting height and height showed −0.0089 decrease (95% CI −0.0157 to −0.0020). Studies reported uniform profiles of adverse events, mostly limited to mild injection-site related issues and no serious complications.</div></div><div><h3>Conclusion</h3><div>This meta-analysis shows that real-world observational data on vosoritide in children with achondroplasia replicate clinical trial findings, with greater gains in linear growth and a similarly favorable safety profile.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101670"},"PeriodicalIF":6.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804417","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":"https://doi.org/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 : 2025-12-17DOI: 10.1016/j.gim.2025.101668
Yuda Wei , Kai Liu , Changrui Mi , Jing Yu , Ruopeng Sun , Shengxing Miao , Haiqi Li , Huili Xue , Xiaxia Liu , Yanyan Hu , Yongzhen Qi , Jie Zhang , Lili Tong , Chen Zhao , Liangqian Jiang , Juan Teng , Xingzhu Geng , Chengcheng Gai , Hongyan Xu , Lin Li , Xiangyu Zhao
Purpose
Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease.
Methods
To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants’ blood and heterologous cell system.
Results
We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling.
Conclusion
Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.
{"title":"Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy","authors":"Yuda Wei , Kai Liu , Changrui Mi , Jing Yu , Ruopeng Sun , Shengxing Miao , Haiqi Li , Huili Xue , Xiaxia Liu , Yanyan Hu , Yongzhen Qi , Jie Zhang , Lili Tong , Chen Zhao , Liangqian Jiang , Juan Teng , Xingzhu Geng , Chengcheng Gai , Hongyan Xu , Lin Li , Xiangyu Zhao","doi":"10.1016/j.gim.2025.101668","DOIUrl":"10.1016/j.gim.2025.101668","url":null,"abstract":"<div><h3>Purpose</h3><div>Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the <em>GSPT2</em> gene, located at Xp11.22, has not yet been associated with any Mendelian disease.</div></div><div><h3>Methods</h3><div>To establish genotype-phenotype associations between <em>GSPT2</em> and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants’ blood and heterologous cell system.</div></div><div><h3>Results</h3><div>We described 6 individuals from 6 unrelated families carrying hemizygous variants in <em>GSPT2</em> with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. <em>GSPT2</em> is preferentially enriched in the brain and cerebellum compared with other tissues. <em>GSPT2</em>-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in <em>GSPT2</em>-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (<em>CACNA1B</em>, etc) in <em>GSPT2</em>-knockout cells and further confirmed these findings with proteomic profiling.</div></div><div><h3>Conclusion</h3><div>Our data suggest a putative <em>GSPT2</em>-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101668"},"PeriodicalIF":6.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794077","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 : 2025-12-17DOI: 10.1016/j.gim.2025.101665
Whiwon Lee , Joyce Yan , Katharine Fooks , Melanie Barwick , Mark Dobrow , Jan M. Friedman , Christian R. Marshall , Robin Z. Hayeems
Purpose
The global demand for clinical genome-wide sequencing (GWS) continues to grow. This study describes the global landscape of genetic service delivery and the barriers and facilitators to implementing clinical GWS.
Methods
A scoping review was conducted using MEDLINE and Embase (January 2009-July 2025) to identify studies related to genetic service delivery, exome and genome sequencing, and implementation.
Results
Ninety-six articles representing 35 countries were analyzed using the updated Consolidated Framework for Implementation Research. The most frequently reported barriers were within the outer setting: insufficient Local Conditions (ie, genetics workforce shortage; 54/96, 56%), limited Financing (29/96, 30%), and lack of national Policies and Laws (regulations) for genomic testing (20/96, 21%). Negative Local Attitudes about genomics were reported as a barrier in 11 South American, Middle Eastern, Asian, and African countries. Identified outer setting facilitators included Partnerships and Connections between interested parties (eg, government, academic institutions; 14/96, 15%) and dedicated Funding for national genomics initiatives (6/96, 6%).
Conclusion
This scoping review identified common barriers to implementing GWS across countries with varying capacities for delivering these services. Findings may help countries to anticipate barriers, leverage facilitators, and develop strategies for implementing genomic testing and services.
{"title":"Barriers and facilitators to implementing clinical genome-wide sequencing: A scoping review of the global landscape","authors":"Whiwon Lee , Joyce Yan , Katharine Fooks , Melanie Barwick , Mark Dobrow , Jan M. Friedman , Christian R. Marshall , Robin Z. Hayeems","doi":"10.1016/j.gim.2025.101665","DOIUrl":"10.1016/j.gim.2025.101665","url":null,"abstract":"<div><h3>Purpose</h3><div>The global demand for clinical genome-wide sequencing (GWS) continues to grow. This study describes the global landscape of genetic service delivery and the barriers and facilitators to implementing clinical GWS.</div></div><div><h3>Methods</h3><div>A scoping review was conducted using MEDLINE and Embase (January 2009-July 2025) to identify studies related to genetic service delivery, exome and genome sequencing, and implementation.</div></div><div><h3>Results</h3><div>Ninety-six articles representing 35 countries were analyzed using the updated Consolidated Framework for Implementation Research. The most frequently reported barriers were within the outer setting: insufficient Local Conditions (ie, genetics workforce shortage; 54/96, 56%), limited Financing (29/96, 30%), and lack of national Policies and Laws (regulations) for genomic testing (20/96, 21%). Negative Local Attitudes about genomics were reported as a barrier in 11 South American, Middle Eastern, Asian, and African countries. Identified outer setting facilitators included Partnerships and Connections between interested parties (eg, government, academic institutions; 14/96, 15%) and dedicated Funding for national genomics initiatives (6/96, 6%).</div></div><div><h3>Conclusion</h3><div>This scoping review identified common barriers to implementing GWS across countries with varying capacities for delivering these services. Findings may help countries to anticipate barriers, leverage facilitators, and develop strategies for implementing genomic testing and services.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101665"},"PeriodicalIF":6.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794074","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}
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