Pub Date : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub Date: 2026-03-04DOI: 10.1016/j.gim.2025.101657
Kristy Lee , Christa Lese Martin , David T. Miller
{"title":"Response to Deuitch et al","authors":"Kristy Lee , Christa Lese Martin , David T. Miller","doi":"10.1016/j.gim.2025.101657","DOIUrl":"10.1016/j.gim.2025.101657","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101657"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372461","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 : 2026-03-01Epub 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":"2026-03-01","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}
Pub Date : 2026-03-01Epub Date: 2025-12-17DOI: 10.1016/j.gim.2025.101667
Eva Martinez , Jillian Serrano , Siwaar Abouhala , Ashana Neale , Grace VanNoy , Heidi L. Rehm , Melanie O’Leary , Anne O’Donnell-Luria , Monica H. Wojcik
Purpose
Rare disease genomic research suffers from a lack of diverse participation. We therefore implemented and evaluated a multi-faceted intervention to support recruitment of populations previously underrepresented by race, ethnicity, primary language, household income, education level, or rural residence to the Rare Genomes Project.
Methods
For a prospective cohort, we tracked completion of our enrollment processes supported by interventions including clinician engagement, language support, proactive and flexible participant contact, and use of mobile phlebotomy. Participants were offered a survey upon enrollment to assess values and priorities.
Results
In total, 161 of 195 (83%) participants completed enrollment. High-yield interventions included clinician referral forms and increased staff assistance. Genome sequencing data have been generated for 133 participants, with a diagnosis found for 17 (13%) and candidate for 23 (17%) thus far. Most diagnosed participants (13/17, 76%) benefited from clinician rather than self-referral. Perceived importance of a genetic diagnosis was ranked very/extremely high for 81 of 96 (84%) of participants. Spanish primary language was associated with higher perceived importance and high income with lower perceived importance, although only income remained significant in a multivariable model.
Conclusion
Overall, our equity-focused initiative enabled enrollment of participants from populations previously underrepresented in rare disease genomic research and offers insight into potential motivators.
{"title":"Equity-focused implementation to enhance access to rare disease genomic research and understand diverse perspectives","authors":"Eva Martinez , Jillian Serrano , Siwaar Abouhala , Ashana Neale , Grace VanNoy , Heidi L. Rehm , Melanie O’Leary , Anne O’Donnell-Luria , Monica H. Wojcik","doi":"10.1016/j.gim.2025.101667","DOIUrl":"10.1016/j.gim.2025.101667","url":null,"abstract":"<div><h3>Purpose</h3><div>Rare disease genomic research suffers from a lack of diverse participation. We therefore implemented and evaluated a multi-faceted intervention to support recruitment of populations previously underrepresented by race, ethnicity, primary language, household income, education level, or rural residence to the Rare Genomes Project.</div></div><div><h3>Methods</h3><div>For a prospective cohort, we tracked completion of our enrollment processes supported by interventions including clinician engagement, language support, proactive and flexible participant contact, and use of mobile phlebotomy. Participants were offered a survey upon enrollment to assess values and priorities.</div></div><div><h3>Results</h3><div>In total, 161 of 195 (83%) participants completed enrollment. High-yield interventions included clinician referral forms and increased staff assistance. Genome sequencing data have been generated for 133 participants, with a diagnosis found for 17 (13%) and candidate for 23 (17%) thus far. Most diagnosed participants (13/17, 76%) benefited from clinician rather than self-referral. Perceived importance of a genetic diagnosis was ranked very/extremely high for 81 of 96 (84%) of participants. Spanish primary language was associated with higher perceived importance and high income with lower perceived importance, although only income remained significant in a multivariable model.</div></div><div><h3>Conclusion</h3><div>Overall, our equity-focused initiative enabled enrollment of participants from populations previously underrepresented in rare disease genomic research and offers insight into potential motivators.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101667"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794014","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 : 2026-03-01Epub Date: 2026-03-04DOI: 10.1016/j.gim.2025.101656
Natalie T. Deuitch , Paul P. Liu , David J. Young , David Wu , Lucy A. Godley
{"title":"Correspondence on “ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)” by Lee et al","authors":"Natalie T. Deuitch , Paul P. Liu , David J. Young , David Wu , Lucy A. Godley","doi":"10.1016/j.gim.2025.101656","DOIUrl":"10.1016/j.gim.2025.101656","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101656"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372905","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 : 2026-03-01Epub Date: 2026-01-06DOI: 10.1016/j.gim.2025.101681
Rory J. Tinker , Lucas D. Richter , Yutaka Furuta , Cathy Shyr , Sherwin M. Shirazi , Jennifer Sucre , Luke A. Gatta , John A. Phillips 3rd , Josh F. Peterson , Lisa Bastarache
Purpose
The effect of Mendelian disorders on pregnancy and neonatal outcomes is poorly understood because of their rarity and the challenge of compiling complete prenatal and postnatal records.
Methods
Using electronic health records from a single academic center, we developed a retrospective cohort of maternal-infant dyads. Cases were mothers with molecularly confirmed Mendelian disorders paired with live-born infants; controls had no documented genetic disease. Outcomes were evaluated overall, by organ system, and by individual disorder.
Results
The cohort included 58,912 dyads, 241 with genetic diagnoses and 58,671 controls. Although overall outcomes were generally favorable, mothers with genetic disorders had higher rates of cesarean delivery and neonatal intensive care unit admission, earlier gestational age, and lower Apgar scores. Neonatal risks were greatest among neurological and cardiovascular disorders. Known associations were replicated, including increased neonatal intensive care unit admission in 22q11.2 deletion syndrome, cesarean delivery in Turner syndrome, and gestational diabetes in cystic fibrosis. We also provided descriptive electronic-health-record-based case reports and case series for 35 disorders previously lacking published pregnancy outcome data.
Conclusion
This study identifies elevated perinatal risks in specific Mendelian disease groups and demonstrates how electronic-health-record-linked data can support prenatal counseling, risk stratification, and individualized care for individuals with genetic disorders.
{"title":"Evaluating pregnancy and neonatal outcomes in mothers with genetic disease using electronic health care records","authors":"Rory J. Tinker , Lucas D. Richter , Yutaka Furuta , Cathy Shyr , Sherwin M. Shirazi , Jennifer Sucre , Luke A. Gatta , John A. Phillips 3rd , Josh F. Peterson , Lisa Bastarache","doi":"10.1016/j.gim.2025.101681","DOIUrl":"10.1016/j.gim.2025.101681","url":null,"abstract":"<div><h3>Purpose</h3><div>The effect of Mendelian disorders on pregnancy and neonatal outcomes is poorly understood because of their rarity and the challenge of compiling complete prenatal and postnatal records.</div></div><div><h3>Methods</h3><div>Using electronic health records from a single academic center, we developed a retrospective cohort of maternal-infant dyads. Cases were mothers with molecularly confirmed Mendelian disorders paired with live-born infants; controls had no documented genetic disease. Outcomes were evaluated overall, by organ system, and by individual disorder.</div></div><div><h3>Results</h3><div>The cohort included 58,912 dyads, 241 with genetic diagnoses and 58,671 controls. Although overall outcomes were generally favorable, mothers with genetic disorders had higher rates of cesarean delivery and neonatal intensive care unit admission, earlier gestational age, and lower Apgar scores. Neonatal risks were greatest among neurological and cardiovascular disorders. Known associations were replicated, including increased neonatal intensive care unit admission in 22q11.2 deletion syndrome, cesarean delivery in Turner syndrome, and gestational diabetes in cystic fibrosis. We also provided descriptive electronic-health-record-based case reports and case series for 35 disorders previously lacking published pregnancy outcome data.</div></div><div><h3>Conclusion</h3><div>This study identifies elevated perinatal risks in specific Mendelian disease groups and demonstrates how electronic-health-record-linked data can support prenatal counseling, risk stratification, and individualized care for individuals with genetic disorders.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101681"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933013","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 : 2026-03-01Epub Date: 2026-03-04DOI: 10.1016/j.gim.2025.101663
Michael Allison , Terresa Adams , Jennifer Foster , Kathy Hale , Dominique Tapplar
{"title":"Correspondence on “Sequencing and health data resource of children of African ancestry”","authors":"Michael Allison , Terresa Adams , Jennifer Foster , Kathy Hale , Dominique Tapplar","doi":"10.1016/j.gim.2025.101663","DOIUrl":"10.1016/j.gim.2025.101663","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101663"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372335","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 : 2026-03-01Epub Date: 2026-01-30DOI: 10.1016/j.gim.2025.101659
Tuya Pal , Joseph Christopher , Esteban Astiazaran-Symonds , William D. Foulkes , Paul James , Susan Klugman , Allison Kurian , Julie Mak , Alvaro Monteiro , Mark Robson , Marc Tischkowitz , Douglas R. Stewart , Helen Hanson , ACMG Professional Practice and Guidelines Committee
{"title":"Consideration of inherited cancer risk on a continuum: An international and multidisciplinary perspective: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Tuya Pal , Joseph Christopher , Esteban Astiazaran-Symonds , William D. Foulkes , Paul James , Susan Klugman , Allison Kurian , Julie Mak , Alvaro Monteiro , Mark Robson , Marc Tischkowitz , Douglas R. Stewart , Helen Hanson , ACMG Professional Practice and Guidelines Committee","doi":"10.1016/j.gim.2025.101659","DOIUrl":"10.1016/j.gim.2025.101659","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101659"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092935","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 : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.gim.2025.101661
Maria Cerminara , Giovanni Spirito , Luca Pandolfini , Silvia Boeri , Giulia Rosti , Margherita Mancardi , Livia Pisciotta , Marco Fontana , Alessandra Bianchi , Iris Chen , Loretta Ferrera , Francesco Caroli , Marco Di Duca , Andrea Cavalli , Maria Teresa Divizia , Elisa De Grandis , Silvia Casabona , Sara Trova , Diego Vozzi , Antonio Amoroso , Aldamaria Puliti
Purpose
Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression.
Methods
We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband.
Results
Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes.
Conclusion
Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.
{"title":"Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions","authors":"Maria Cerminara , Giovanni Spirito , Luca Pandolfini , Silvia Boeri , Giulia Rosti , Margherita Mancardi , Livia Pisciotta , Marco Fontana , Alessandra Bianchi , Iris Chen , Loretta Ferrera , Francesco Caroli , Marco Di Duca , Andrea Cavalli , Maria Teresa Divizia , Elisa De Grandis , Silvia Casabona , Sara Trova , Diego Vozzi , Antonio Amoroso , Aldamaria Puliti","doi":"10.1016/j.gim.2025.101661","DOIUrl":"10.1016/j.gim.2025.101661","url":null,"abstract":"<div><h3>Purpose</h3><div>Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as <em>FAN1</em>, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression.</div></div><div><h3>Methods</h3><div>We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband.</div></div><div><h3>Results</h3><div>Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101661"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145722532","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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