Genetics in Medicine最新文献

{"title":"No association between FMR1 premutation and either ADHD or anxiety in 53,707 women undergoing genetic testing for family planning purposes","authors":"Liraz Klausner ,&nbsp;Shai Carmi ,&nbsp;Shay Ben-Shachar ,&nbsp;Noa Lev-El Halabi ,&nbsp;Lina Basel-Salmon ,&nbsp;Dana Brabbing-Goldstein","doi":"10.1016/j.gim.2025.101428","DOIUrl":"10.1016/j.gim.2025.101428","url":null,"abstract":"<div><h3>Purpose</h3><div><em>FMR1</em> premutation has been inconsistently associated with neuropsychiatric phenotypes, possibly because of ascertainment bias. We investigated the association between <em>FMR1</em> premutation and attention deficit hyperactivity disorder (ADHD), anxiety, and other psychiatric disorders in large-scale population-based genetic carrier screening data.</div></div><div><h3>Methods</h3><div>We defined premutation as having 58 to 200 CGG repeats. Phenotypes were identified in linked electronic medical records via formal diagnoses or relevant medication purchases. As a positive control, we assessed premature ovarian insufficiency and elevated follicle-stimulating hormone levels before the age of 40.</div></div><div><h3>Results</h3><div>Our study included 53,707 women, among them 464 premutation heterozygotes. The premutation status was associated with premature ovarian insufficiency (hazard ratio [HR]: 4.08; 95% CI: 2.16-7.72) and high follicle-stimulating hormone (HR: 3.43; 95% CI: 2.65-4.43) but not with ADHD (HR: 1.08; 95% CI: 0.75-1.56), anxiety (HR: 0.74; 95% CI: 0.53-1.04), anxiety and depression (HR: 0.86; 95% CI: 0.69-1.07), and other psychiatric disorders (HR: 1.22; 95% CI: 0.73-2.03). Our study was sufficiently powered to detect HR approximately 1.5-2 or higher.</div></div><div><h3>Conclusion</h3><div>No association was found between <em>FMR1</em> premutation status and either ADHD or anxiety. Although our study design avoided bias toward affected families, participants may be healthier than average, and small effects cannot be excluded.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101428"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803094","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":"Non-coding single-nucleotide and structural variants affecting the EYS putative promoter cause autosomal recessive retinitis pigmentosa","authors":"Tamar Hayman ,&nbsp;Shai Ovadia ,&nbsp;Jaya Krishnan ,&nbsp;Manon Bouckaert ,&nbsp;Daan M. Panneman ,&nbsp;Milton English ,&nbsp;Johanna Valensi ,&nbsp;Frans P.M. Cremers ,&nbsp;Tamar Ben Yosef ,&nbsp;L. Ingeborgh van den Born ,&nbsp;Suzanne E. de Bruijn ,&nbsp;Susanne Roosing ,&nbsp;Eyal Banin ,&nbsp;Samer Khateb ,&nbsp;Ruth Ashery-Padan ,&nbsp;Frauke Coppieters ,&nbsp;Anand Swaroop ,&nbsp;Dror Sharon","doi":"10.1016/j.gim.2025.101427","DOIUrl":"10.1016/j.gim.2025.101427","url":null,"abstract":"<div><h3>Purpose</h3><div>Variants in untranslated genomic regions are difficult to identify as pathogenic but are capable of causing disease by interfering with gene expression. This study aimed to characterize the effect of variants identified in the 5′-untranslated region of <em>EYS</em> in patients with autosomal recessive retinitis pigmentosa (RP).</div></div><div><h3>Methods</h3><div>Variant screening included gene panels, Sanger, exome, and genome sequencing. Functional validation included an electrophoretic mobility shift assay and various luciferase assays.</div></div><div><h3>Results</h3><div>Patients with RP from 6 <em>EYS</em> biallelic Arab-Muslim families harbored a 5′ noncoding <em>EYS</em> variant, c.-453G&gt;T, and 4 harbored a structural variant affecting the 5′ noncoding exons. Electrophoretic mobility shift assay analysis revealed an effect on binding of transcription factors for c.-453G&gt;T and a neighboring variant c.-454G&gt;T. Dual luciferase assays using overexpression of various transcription factors showed distinct effects on expression. c.-453G&gt;T was associated with higher luciferase expression with CRX overexpression and c.-454G&gt;C with OTX2 overexpression. In addition, the 2 variants were found to influence translation by affecting upstream initiation codons. Interestingly, visual function of <em>EYS</em> RP patients who harbor c.-453G&gt;T are better than those with biallelic null <em>EYS</em> variants.</div></div><div><h3>Conclusion</h3><div>Our analysis revealed both single-nucleotide and structural variants in the <em>EYS</em> promoter as the cause of autosomal recessive RP. These variants may affect <em>EYS</em> expression via a dual mechanism by altering transcription factor binding affinity at the <em>EYS</em> promoter and by affecting upstream open reading frames.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101427"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795088","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":"Biochemical testing for congenital disorders of glycosylation: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Patricia L. Hall ,&nbsp;Christina Lam ,&nbsp;Lynne Wolfe ,&nbsp;Andrew Edmondson ,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101328","DOIUrl":"10.1016/j.gim.2024.101328","url":null,"abstract":"<div><div>Congenital disorders of glycosylation (CDG) are a large and continually expanding group of disorders that present with a variety of clinical findings and have been linked to over 170 genes. Individually, CDGs are rare; however, the true incidence may be underestimated because of the variability of the clinical findings, and the multiple testing strategies needed to diagnosis them across multiple pathways. Testing for CDGs has evolved over recent years with the availability of high-throughput molecular testing and improved gene discovery techniques. Biochemical testing to detect defects in glycosylated proteins or enzymatic deficiency still plays a critical role in the diagnosis of affected individuals, and both testing modalities are often required to finalize a diagnosis. Emerging therapeutic approaches targeting improvements in glycosylation require reliable and reproducible biochemical testing for therapeutic monitoring, dose adjustment, and avoidance of dose-related side effects. To maintain clinical sensitivity and specificity and to ensure reproducibility across laboratories performing complex biochemical testing, the American College of Medical Genetics and Genomics has developed the following technical standard.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101328"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders","authors":"Elisa Cali ,&nbsp;Tania Quirin ,&nbsp;Clarissa Rocca ,&nbsp;Stephanie Efthymiou ,&nbsp;Antonella Riva ,&nbsp;Dana Marafi ,&nbsp;Maha S. Zaki ,&nbsp;Mohnish Suri ,&nbsp;Roberto Dominguez ,&nbsp;Hasnaa M. Elbendary ,&nbsp;Shahryar Alavi ,&nbsp;Mohamed S. Abdel-Hamid ,&nbsp;Heba Morsy ,&nbsp;Frederic Tran Mau-Them ,&nbsp;Mathilde Nizon ,&nbsp;Pavel Tesner ,&nbsp;Lukáš Ryba ,&nbsp;Faisal Zafar ,&nbsp;Nuzhat Rana ,&nbsp;Nebal W. Saadi ,&nbsp;Reza Maroofian","doi":"10.1016/j.gim.2024.101251","DOIUrl":"10.1016/j.gim.2024.101251","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aims to comprehensively delineate the phenotypic spectrum of <em>ACTL6B</em>-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.</div></div><div><h3>Methods</h3><div>We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of <em>ACTL6B</em> in ribosome biogenesis.</div></div><div><h3>Results</h3><div>Biallelic variants in <em>ACTL6B</em> are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing.</div></div><div><h3>Conclusion</h3><div>This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of <em>ACTL6B</em>-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of “ribosomopathies.”</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101251"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique signatures of highly constrained genes across publicly available genomic databases","authors":"Klaus Schmitz-Abe ,&nbsp;Qifei Li ,&nbsp;Sunny Greene ,&nbsp;Michela Borrelli ,&nbsp;Shiyu Luo ,&nbsp;Madesh C. Ramesh ,&nbsp;Pankaj B. Agrawal","doi":"10.1016/j.gim.2025.101413","DOIUrl":"10.1016/j.gim.2025.101413","url":null,"abstract":"<div><h3>Purpose</h3><div>Publicly available genomic databases are critical in understanding human genetic variation. They also provide unique insights into patterns of genetic constraints and their relationship with human disease.</div></div><div><h3>Methods</h3><div>We utilized one of the largest publicly available databases, Genome Aggregate Database, to determine genes that are highly constrained for only loss-of-function, only missense, and both loss-of-function/missense variants. We identified their unique signatures and explored their causal relationship with human diseases. Those genes were also evaluated for chromosomal location, tissue-level expression, Gene Ontology analysis, and gene family categorization using multiple publicly available databases.</div></div><div><h3>Results</h3><div>We identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways for those constrained genes associated with human disease. In addition, we identified genes that are currently not known to cause human disease, which may be excellent gene discovery candidates.</div></div><div><h3>Conclusion</h3><div>We elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins. The findings can also advance research in rare diseases.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101413"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691989","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":"Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa","authors":"Lorenzo Bianco ,&nbsp;Julien Navarro ,&nbsp;Christelle Michiels ,&nbsp;Riccardo Sangermano ,&nbsp;Christel Condroyer ,&nbsp;Aline Antonio ,&nbsp;Alessio Antropoli ,&nbsp;Camille Andrieu ,&nbsp;Emily M. Place ,&nbsp;Eric A. Pierce ,&nbsp;Said El Shamieh ,&nbsp;Vasily Smirnov ,&nbsp;Vasiliki Kalatzis ,&nbsp;Luke Mansard ,&nbsp;Anne-Françoise Roux ,&nbsp;Béatrice Bocquet ,&nbsp;José-Alain Sahel ,&nbsp;Isabelle Meunier ,&nbsp;Kinga M. Bujakowska ,&nbsp;Isabelle Audo ,&nbsp;Christina Zeitz","doi":"10.1016/j.gim.2025.101418","DOIUrl":"10.1016/j.gim.2025.101418","url":null,"abstract":"<div><h3>Purpose</h3><div>Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (<em>RPGR</em>, <em>RP2</em>, and <em>OFD1</em>), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP.</div></div><div><h3>Methods</h3><div>Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays.</div></div><div><h3>Results</h3><div>We identified 4 rare single-nucleotide variants in <em>IDH3G</em> (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. <em>IDH3G</em> encodes the <em>γ</em> subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in <em>IDH3A</em> and <em>IDH3B,</em> encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly through partial loss of enzymatic activity and mitochondrial function.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that variants in <em>IDH3G</em> are a novel cause of X-linked RP.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101418"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676897","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":"Clinical signatures of SYNGAP1-related disorders through data integration","authors":"Jillian L. McKee ,&nbsp;Jan H. Magielski ,&nbsp;Julie Xian ,&nbsp;Stacey Cohen ,&nbsp;Jonathan Toib ,&nbsp;Alicia Harrison ,&nbsp;Chen Chen ,&nbsp;Dan Kim ,&nbsp;Aakash Rathod ,&nbsp;Elise Brimble ,&nbsp;Nasha Fitter ,&nbsp;J. Michael Graglia ,&nbsp;Kathryn A. Helde ,&nbsp;Sarah McKeown Ruggiero ,&nbsp;Michael J. Boland ,&nbsp;Benjamin L. Prosser ,&nbsp;Rob Sederman ,&nbsp;Ingo Helbig","doi":"10.1016/j.gim.2025.101419","DOIUrl":"10.1016/j.gim.2025.101419","url":null,"abstract":"<div><h3>Purpose</h3><div><em>SYNGAP1</em> is a genetic neurodevelopmental disorder characterized by generalized epilepsy, autism, and intellectual disability. Despite a comparatively high prevalence, the longitudinal landscape remains relatively unexplored, and complete characterization is essential for clinical trial readiness.</div></div><div><h3>Methods</h3><div>We combined electronic medical record data (<em>n</em> = 158) with insurance claims data (<em>n</em> = 246) to evaluate longitudinal progression of symptoms.</div></div><div><h3>Results</h3><div>Phenotypes associated with <em>SYNGAP1</em> included behavioral abnormalities (odds ratio [OR]: 12.35, 95% CI: 9.21-16.78), generalized-onset seizures (OR: 1.56, 95% CI: 1.20-2.02), autism (OR: 12.23, 95% CI: 9.29-16.24), and a developmental profile with prominent deficits in verbal skill acquisition. Several clinical features showed distinct age-related patterns, such as a more than 5-fold risk of autistic behavior emerging between 27 and 30 months. Generalized-onset seizures were significantly increased (OR: 4.05, 95% CI: 2.02-7.59) after 3 years of age and persisted over time. Valproic acid and clobazam were commonly used for epilepsy treatment, whereas risperidone, aripiprazole, and guanfacine were commonly used for behavior management. Valproate and lamotrigine were more effective at reducing seizure frequencies or maintaining seizure freedom than other antiseizure medications.</div></div><div><h3>Conclusion</h3><div>We delineated the seizure, developmental, and behavioral trajectories in <em>SYNGAP1-</em>related disorders, to improve diagnosis, prognosis, and clinical care, and facilitating clinical trial readiness.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101419"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676864","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":"Primary care providers’ perspectives on receiving opportunistic genomic results from a national study: The Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study","authors":"Anna L. Johannsen ,&nbsp;Morgan E. Danowski ,&nbsp;Kailyn E. Sitter ,&nbsp;Charlene L. Preys ,&nbsp;Haley L. Gerety ,&nbsp;Charles A. Brunette ,&nbsp;Kurt D. Christensen ,&nbsp;J. Michael Gaziano ,&nbsp;Joshua W. Knowles ,&nbsp;Sumitra Muralidhar ,&nbsp;Amy C. Sturm ,&nbsp;Yan V. Sun ,&nbsp;Stacey B. Whitbourne ,&nbsp;Thomas Yi ,&nbsp;The VA Million Veteran Program,&nbsp;Jason L. Vassy","doi":"10.1016/j.gim.2025.101416","DOIUrl":"10.1016/j.gim.2025.101416","url":null,"abstract":"<div><h3>Purpose</h3><div>Patients are increasingly obtaining genetic health information and integrating it into their care with the help of their primary care provider (PCP). However, PCPs may not be adequately prepared to effectively utilize genetic results. Across the Veterans Health Administration health system, the Million Veteran Program Return Of Actionable Results-Familial Hypercholesterolemia (MVP-ROAR-FH) Study clinically confirms and returns genetic results associated with familial hypercholesterolemia (FH), identified in a national biobank program.</div></div><div><h3>Methods</h3><div>PCPs who received their patient’s genetic results through the MVP-ROAR-FH study were invited to participate in semistructured interviews, which explored PCPs’ familiarity with FH, how the results affected medical management, and suggestions for process improvement. Interviews were transcribed and analyzed using directed content analysis and constant comparison methods to identify key themes.</div></div><div><h3>Results</h3><div>Interviews with 9 PCPs revealed varied levels of familiarity with genetic testing and FH. Most PCPs did not distinguish FH from common high cholesterol issues and already used similar treatment approaches. Many PCPs did not recall receiving results from the MVP-ROAR-FH study. Alerts in medical records were deemed effective for communicating results. PCPs valued genetics in informing patient care and identifying at-risk family members but noted several implementation barriers, such as additional workload and unclear medical management benefits. Recommendations for improving results disclosure included simplifying the genetic testing report and associated support documents.</div></div><div><h3>Conclusion</h3><div>The study represents the first investigation into PCPs’ experiences with receiving genetic test results from a biobank linked to a national healthcare system. Results suggest that PCPs generally view genetic testing as beneficial, although they may not significantly alter medical management. PCPs expressed that integrating genetics into routine care may be burdensome and require additional training, which may not be practical. The study underscores the need for accessible genetic information, which could be aided by specialized support roles or different clinical specialties assisting with incorporating genetic results into patient care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101416"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691986","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":"Financial assistance programs for genetic testing: Effective, ethical, and sustainable pathways to improving access disparities?","authors":"Emily Hammad Mrig ,&nbsp;Kathryn A. Phillips ,&nbsp;Mark Schlesinger","doi":"10.1016/j.gim.2025.101417","DOIUrl":"10.1016/j.gim.2025.101417","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101417"},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676891","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":"Systematic method for classifying multiple congenital anomaly cases in electronic health records","authors":"Elly Brokamp ,&nbsp;Tyne Miller-Fleming ,&nbsp;Alexandra Scalici ,&nbsp;Gillian Hooker ,&nbsp;Rizwan Hamid ,&nbsp;Digna Velez Edwards ,&nbsp;Wendy K. Chung ,&nbsp;Yuan Luo ,&nbsp;Krzysztof Kiryluk ,&nbsp;Nita A. Limidi ,&nbsp;Nikhil K. Khankari ,&nbsp;Nancy J. Cox ,&nbsp;Lisa Bastarache ,&nbsp;Megan M. Shuey","doi":"10.1016/j.gim.2025.101415","DOIUrl":"10.1016/j.gim.2025.101415","url":null,"abstract":"<div><h3>Purpose</h3><div>Congenital anomalies (CAs) affect approximately 3% of live births and are the leading cause of infant morbidity and mortality. Many individuals have multiple CAs (MCA), a constellation of 2 or more unrelated CAs; yet, there is no consensus on how to systematically identify these individuals in electronic health records (EHRs). We developed a scalable method to characterize MCA in the EHR, allowing for the dramatic improvement of our understanding of the genetic and epidemiologic underpinnings of MCA.</div></div><div><h3>Methods</h3><div>From the Vanderbilt University Medical Center’s anonymized EHR database, we evaluated 3 different approaches for classifying MCA, including a novel approach that removed minor vs major differentiation and their associated clinical utilization and population characteristics. Using phenome-wide association studies, we assessed the phenome associated with previously classified minor CAs.</div></div><div><h3>Results</h3><div>Our proposed universal method for MCA identification in the EHR is accurate (positive predictive value = 97.1%), associated with heightened hospital utilization (41% receiving inpatient care), and captures granular patterns of CAs. A secondary application of our method was done in 2 separate cohorts.</div></div><div><h3>Conclusion</h3><div>We developed a method to comprehensively identify individuals with MCA in the EHR, allowing researchers to better investigate the genetic etiologies of MCA. This method can be applied across EHR databases with billing codes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 6","pages":"Article 101415"},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673827","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}