Genetics in Medicine最新文献

{"title":"Two-tiered newborn screening for infantile Krabbe disease allows timely treatment initiation and avoids false-positive results","authors":"Patricia L. Hall,&nbsp;Amy L. White,&nbsp;Dawn Peck,&nbsp;Gisele Pino,&nbsp;April Studinski,&nbsp;Dimitar Gavrilov,&nbsp;Devin Oglesbee,&nbsp;Matthew J. Schultz,&nbsp;Silvia Tortorelli,&nbsp;Dietrich Matern","doi":"10.1016/j.gim.2025.101572","DOIUrl":"10.1016/j.gim.2025.101572","url":null,"abstract":"<div><h3>Purpose</h3><div>Infantile Krabbe disease (IKD) is a severe, progressive neurological disorder that was recently added to the Recommended Uniform Screening Panel in the United States. IKD is a critical condition that requires a hematopoietic stem cell transplant, preferably by 30 days of age. This study examines whether the 2-tier newborn screening (NBS) strategy (psychosine [PSY] analysis when enzyme activity is low) causes clinically relevant delays compared with PSY measured at a first clinical follow-up visit.</div></div><div><h3>Methods</h3><div>We reviewed the PSY analyses performed over a 6-year period on dried blood spots on infants &lt; 28 days old. Results were sorted by the ordering site and final diagnosis.</div></div><div><h3>Results</h3><div>On average, infants with a positive NBS for IKD that included abnormal PSY received their diagnosis 7 days sooner than whose PSY testing was initiated during follow-up. Hematopoietic stem cell transplant occurred by the 36th day of life, on average, for cases with IKD detected by 2-tiered NBS.</div></div><div><h3>Conclusion</h3><div>Effective NBS for Krabbe disease requires the use of PSY as a second-tier test, allowing for timely initiation of treatment while virtually eliminating false-positive results. PSY should be included in NBS algorithms for Krabbe disease, and timeliness metrics need to be adjusted.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 4","pages":"Article 101572"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correspondence on “COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management” by Tambala et al","authors":"Ciara McCormick ,&nbsp;John Snelgrove","doi":"10.1016/j.gim.2026.102528","DOIUrl":"10.1016/j.gim.2026.102528","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 4","pages":"Article 102528"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147656459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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":"28 4","pages":"Article 101669"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","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}

{"title":"Response to Amalia","authors":"Elisabeth Stögmann ,&nbsp;Theresa König","doi":"10.1016/j.gim.2026.101689","DOIUrl":"10.1016/j.gim.2026.101689","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 4","pages":"Article 101689"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147656461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder","authors":"Ali H. Bereshneh ,&nbsp;Kirkland A. Wilson ,&nbsp;Xueyang Pan ,&nbsp;Shabab B. Hannan ,&nbsp;Megan A. Cooper ,&nbsp;Jullianne Diaz ,&nbsp;Eyby Leon ,&nbsp;Tiana M. Moses ,&nbsp;Mahshid S. Azamian ,&nbsp;Daryl A. Scott ,&nbsp;Ping Yee Billie Au ,&nbsp;Juan Pablo Appendino ,&nbsp;Ingrid E. Scheffer ,&nbsp;Antony Kaspi ,&nbsp;Melanie Bahlo ,&nbsp;Michael S. Hildebrand ,&nbsp;Angela T. Morgan ,&nbsp;Ekanem Ekure","doi":"10.1016/j.gim.2026.101685","DOIUrl":"10.1016/j.gim.2026.101685","url":null,"abstract":"<div><h3>Purpose</h3><div><em>RAPGEF2</em> encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. <em>RAPGEF2</em> is highly intolerant to loss-of-function variants. We report 5 de novo heterozygous variants in <em>RAPGEF2</em> in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants.</div></div><div><h3>Methods</h3><div>We generated a <em>Kozak-GAL4</em> null allele of the Drosophila ortholog of <em>RAPGEF2</em>, <em>PDZ-GEF</em>, and used the allele to determine the gene expression pattern as well as the loss-of-function phenotypes. We expressed the reference and variant <em>RAPGEF2</em> in <em>PDZ-GEF</em> mutant background to conduct “humanization” studies.</div></div><div><h3>Results</h3><div>Our experiments show that <em>PDZ-GEF</em> is expressed in the central nervous system. Loss of <em>PDZ-GEF</em> leads to severe locomotion defects, aberrant microtubular stability in motor neuron axons, and synaptic overgrowth at neuromuscular junctions in third instar larvae. Mutant animals are lethal at various developmental stages. Importantly, the neurodevelopmental phenotypes can be rescued by expression of the human <em>RAPGEF2</em> reference cDNA but not by any of the variants.</div></div><div><h3>Conclusion</h3><div>Our findings provide functional evidence that the tested <em>RAPGEF2</em> variants are loss-of-function alleles and that the <em>RAPGEF2</em> variants are associated with a neurodevelopmental disorder.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 4","pages":"Article 101685"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correspondence on “Assessing family history and approaches for identifying patients with dementia with diagnostically significant genetic findings” by König et al","authors":"Riza Amalia","doi":"10.1016/j.gim.2026.101688","DOIUrl":"10.1016/j.gim.2026.101688","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 4","pages":"Article 101688"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147656460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Saleem et al","authors":"Irene Valenzuela,&nbsp;Marta Codina-Solà,&nbsp;Eduardo F. Tizzano","doi":"10.1016/j.gim.2026.101687","DOIUrl":"10.1016/j.gim.2026.101687","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 4","pages":"Article 101687"},"PeriodicalIF":6.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Points to consider for the next-generation-sequencing-based detection of copy-number abnormalities (CNAs) and balanced chromosomal rearrangements in neoplastic disorders: A statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Kathleen M. Schieffer ,&nbsp;Cynthia Hawkins ,&nbsp;Nan Jiang ,&nbsp;Ross L. Levine ,&nbsp;Trevor J. Pugh ,&nbsp;Gordana Raca ,&nbsp;Soheil Shams ,&nbsp;Linda B. Baughn ,&nbsp;Yassmine Akkari ,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2025.101658","DOIUrl":"10.1016/j.gim.2025.101658","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101658"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequencing and health data resource of children of African ancestry","authors":"Leah C. Kottyan ,&nbsp;Scott Richards ,&nbsp;Morgan E. Tracy ,&nbsp;Lucinda P. Lawson ,&nbsp;Isabelle C. Kottyan ,&nbsp;Annika Curwin ,&nbsp;Beth Cobb ,&nbsp;Steve Esslinger ,&nbsp;Margaret Gerwe ,&nbsp;James Morgan ,&nbsp;Alka Chandel ,&nbsp;Leksi Travitz ,&nbsp;Yongbo Huang ,&nbsp;Catherine Black ,&nbsp;Agboade Sobowale ,&nbsp;Tinuke Akintobi ,&nbsp;Monica J. Mitchell ,&nbsp;Andrew F. Beck ,&nbsp;Ndidi Unaka ,&nbsp;Michael Seid ,&nbsp;Kenneth M. Kaufman","doi":"10.1016/j.gim.2025.101660","DOIUrl":"10.1016/j.gim.2025.101660","url":null,"abstract":"<div><h3>Purpose</h3><div>Individuals who self-report as Black or African American are historically underrepresented in genome-wide studies of disease risk, a disparity particularly evident in pediatric disease research. To address this gap, Cincinnati Children’s Hospital Medical Center (CCHMC) established a biorepository and developed a comprehensive DNA sequencing resource including 15,684 individuals who self-identified as African American or Black and received care at CCHMC.</div></div><div><h3>Methods</h3><div>Participants were enrolled through the CCHMC Discover Together Biobank and sequenced. Admixture analyses confirmed the genetic ancestry of the cohort, which was then linked to electronic medical records.</div></div><div><h3>Results</h3><div>Genome-wide genotypes from common variants accompanied by medical record-sourced data are available through the Genomic Information Commons. This data set performs well in genetic studies. Specifically, we replicated known associations in sickle-cell disorder (<em>HBB</em>, HGNC:4827, <em>P</em> = 4.05 × 10^-148), anxiety (<em>PLAAT3</em>, HGNC:17825, <em>P</em> = 6.93 × 10^-9), and asthma (<em>PCDH15</em>, HGNC:14674, <em>P</em> = 5.6 × 10^-10), while also identifying novel loci associated with anxiety, asthma, and asthma severity.</div></div><div><h3>Conclusion</h3><div>We present the acquisition and quality of genetic and disease-associated data and present an analytical framework for using this resource. In partnership with a community advisory council, we have codeveloped a valuable framework for data use and future research.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101660"},"PeriodicalIF":6.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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 ,&nbsp;Kai Liu ,&nbsp;Changrui Mi ,&nbsp;Jing Yu ,&nbsp;Ruopeng Sun ,&nbsp;Shengxing Miao ,&nbsp;Haiqi Li ,&nbsp;Huili Xue ,&nbsp;Xiaxia Liu ,&nbsp;Yanyan Hu ,&nbsp;Yongzhen Qi ,&nbsp;Jie Zhang ,&nbsp;Lili Tong ,&nbsp;Chen Zhao ,&nbsp;Liangqian Jiang ,&nbsp;Juan Teng ,&nbsp;Xingzhu Geng ,&nbsp;Chengcheng Gai ,&nbsp;Hongyan Xu ,&nbsp;Lin Li ,&nbsp;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}