Genetics in Medicine最新文献

{"title":"De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies","authors":"Monika Weisz-Hubshman ,&nbsp;Lindsay C. Burrage ,&nbsp;Sharayu V. Jangam ,&nbsp;Jill A. Rosenfeld ,&nbsp;Sandra von Hardenberg ,&nbsp;Anke Bergmann ,&nbsp;Manuela Friederike Richter ,&nbsp;Malgorzata Rydzanicz ,&nbsp;Rafal Ploski ,&nbsp;Agnieszka Stembalska ,&nbsp;Wendy K. Chung ,&nbsp;Rebecca R. Hernan ,&nbsp;Foong Y. Lim ,&nbsp;Theresa Brunet ,&nbsp;Steffen Syrbe ,&nbsp;Boris Keren ,&nbsp;Solveig Heide ,&nbsp;David R. Murdock ,&nbsp;Hongzheng Dai ,&nbsp;Fan Xia ,&nbsp;Brendan Lee","doi":"10.1016/j.gim.2025.101369","DOIUrl":"10.1016/j.gim.2025.101369","url":null,"abstract":"<div><h3>Purpose</h3><div>Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.</div></div><div><h3>Methods</h3><div>Functional consequences of <em>RYBP</em> variants were assessed using in vitro cellular and in vivo <em>Drosophila melanogaster</em> studies.</div></div><div><h3>Results</h3><div>We described 7 individuals with heterozygous de novo variants of <em>RYBP</em> and their clinical findings, including severe developmental delay, dysmorphisms, and multiple congenital anomalies. We showed that all single-nucleotide variants in <em>RYBP</em> localize to the N-terminal domain of the gene, which encodes the zinc-finger domain and ubiquitin-binding moiety. In vitro studies have demonstrated that the <em>RYBP</em> c.132C&gt;G p.(Cys44Trp) variant causes reduced protein expression but does not affect the binding of YY1, RING1B, or ubiquitin. In vivo overexpression studies in <em>Drosophila melanogaster</em> showed a dramatic functional difference between human RYBP and its variant forms, affecting the C44 amino acid residue. DNA methylation studies suggested a possible episignature associated with <em>RYBP</em>-related disorder.</div></div><div><h3>Conclusion</h3><div>Heterozygous de novo variants in <em>RYBP</em> are associated with an identifiable syndromic neurodevelopmental disorder with multiple congenital anomalies.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101369"},"PeriodicalIF":6.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074556","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":"Digital technologies in genetic counseling: Recommendations for a morally sound integration","authors":"Marlies N. van Lingen ,&nbsp;Noor A.A. Giesbertz ,&nbsp;Karin R. Jongsma","doi":"10.1016/j.gim.2025.101370","DOIUrl":"10.1016/j.gim.2025.101370","url":null,"abstract":"<div><div>To address the increasing demand for clinical genetic counseling, digital technologies are currently being developed to increase efficiency and overcome logistical and societal barriers in genetic health care. However, it is not self-evident that genetic technologies will improve the quality of and access to genetic counseling. Moreover, several ethical questions about the appropriate tasks of digital technologies in the genetic care process have been raised, particularly when personal contact is supplemented or even replaced with digital technologies. Ethical reflections on the introduction of digital resources in genetic counseling are scarce. Here, we reflect on 3 central domains in which promises of the digitalization of genetic counseling are generally discussed: (1) promoting patient autonomy and patient-centered care, (2) increasing efficiency, and (3) increasing accessibility. We argue that the benefits of digitalization are not self-evident and are paired with challenges. We conclude by offering 4 recommendations to promote the ethically sound development of digital technologies in genetic health care: (1) specify the intended tasks and expected benefits of the digital technology, (2) identify potential challenges of digitalization, (3) consider the role of end users within the genetic care process, and (4) ensure iterative stakeholder consultation and engagement.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101370"},"PeriodicalIF":6.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074562","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":"Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society","authors":"María José Ariza ,&nbsp;Inmaculada Coca-Prieto ,&nbsp;José Rioja ,&nbsp;Ovidio Muñiz-Grijalvo ,&nbsp;Daniel Zambón-Rados ,&nbsp;Agustín Blanco-Echevarría ,&nbsp;Teresa Arrobas-Velilla ,&nbsp;Javier Delgado-Lista ,&nbsp;David León-Jiménez ,&nbsp;Marta Casañas-Martínez ,&nbsp;Luis Antonio Álvarez-Sala ,&nbsp;Liliana Gutiérrez-Carrasquilla ,&nbsp;Justo Sánchez-Gil ,&nbsp;Mónica Domènech ,&nbsp;Andrés González-Jiménez ,&nbsp;María José Benítez-Toledo ,&nbsp;Javier Espíldora-Hernández ,&nbsp;Emilio Ortega-Martínez de Victoria ,&nbsp;Miguel Ángel Sánchez-Chaparro ,&nbsp;Pedro Valdivielso","doi":"10.1016/j.gim.2025.101365","DOIUrl":"10.1016/j.gim.2025.101365","url":null,"abstract":"<div><h3>Purpose</h3><div>Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases.</div></div><div><h3>Methods</h3><div>245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients.</div></div><div><h3>Results</h3><div>Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the <em>LPL</em>, <em>APOA5</em>, and <em>LMF1</em> genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in <em>LMF1</em> remained as VUS. Additionally, 1 variant in <em>LPL</em> and 2 in <em>GPIHBP1</em> were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations.</div></div><div><h3>Conclusion</h3><div>The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 5","pages":"Article 101365"},"PeriodicalIF":6.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052332","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":"Newborn screening for common genetic variants associated with permanent hearing loss: Implementation in Ontario and review of the first 3 years","authors":"Kristin D. Kernohan ,&nbsp;Lauren Gallagher ,&nbsp;Marie Pigeon ,&nbsp;Ed Yeh ,&nbsp;Melanie Lacaria ,&nbsp;Michelle M. Axford ,&nbsp;Johnna MacCormick ,&nbsp;Vicky Papaioannou ,&nbsp;Nada Quercia ,&nbsp;Charles Rupar ,&nbsp;Kim Zimmerman ,&nbsp;Stacey Weber ,&nbsp;Sharon L. Cushing ,&nbsp;Pranesh Chakraborty","doi":"10.1016/j.gim.2025.101364","DOIUrl":"10.1016/j.gim.2025.101364","url":null,"abstract":"<div><h3>Purpose</h3><div>Early hearing detection and intervention (EHDI) programs using audiometric screening techniques alone have a limited ability to detect noncongenital childhood permanent hearing loss (PHL). In 2019, Ontario launched universal newborn screening (NBS) for PHL risk factors, including congenital cytomegalovirus and 22 common variants in <em>GJB2</em> and <em>SLC26A4</em>. Here, we describe our experience in screening for genetic risk factors.</div></div><div><h3>Methods</h3><div>Ontario newborns who participated in universal newborn hearing screening (UNHS) were offered risk factor screening using dried blood spots (DBS) collected for conventional newborn screening. The screening was conducted using a custom MassArray assay, and positive results were confirmed by Sanger sequencing or polymerase chain reaction. Diagnostic audiological assessments were performed for all screen-positive infants.</div></div><div><h3>Results</h3><div>Of the 412,424 infants screened, 93 had 2 variants in <em>GJB2</em> or <em>SLC26A4.</em> Of these<em>,</em> 72 had confirmed PHL, 20 had normal hearing, and 1 declined follow-up. Thirteen infants with PHL (1 in 31,724; 11.8% of screen positives) were not identified through audiometric testing as they passed (3) or missed (10) the screening. Importantly, among infants who ultimately received cochlear implants, the detection of genetic etiology through NBS led to an accelerated time to diagnosis, assessment, and intervention.</div></div><div><h3>Conclusion</h3><div>Genetic screening has strengthened UNHS and care for infants with or at risk of PHL in Ontario. This study is a step toward the broader inclusion of genomic testing in NBS.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101364"},"PeriodicalIF":6.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023211","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":"Genomic sequencing in diverse and underserved pediatric populations: Parent perspectives on understanding, uncertainty, psychosocial impact, and personal utility of results","authors":"Barbara B. Biesecker ,&nbsp;Sara L. Ackerman ,&nbsp;Kyle B. Brothers ,&nbsp;Kelly M. East ,&nbsp;Ann Katherine M. Foreman ,&nbsp;Lucia A. Hindorff ,&nbsp;Carol R. Horowitz ,&nbsp;Gail P. Jarvik ,&nbsp;Sara J. Knight ,&nbsp;Michael C. Leo ,&nbsp;Donald L. Patrick ,&nbsp;Christine Rini ,&nbsp;Jill O. Robinson ,&nbsp;Nuriye Nalan Sahin-Hodoglugil ,&nbsp;Anne Slavotinek ,&nbsp;Sabrina A. Suckiel ,&nbsp;David L. Veenstra ,&nbsp;Randi E. Zinberg ,&nbsp;Jessica Ezzell Hunter","doi":"10.1016/j.gim.2025.101363","DOIUrl":"10.1016/j.gim.2025.101363","url":null,"abstract":"<div><h3>Purpose</h3><div>Limited evidence evaluates parents’ perceptions of their child’s clinical genome-scale sequencing (GS) results, particularly among individuals from medically underserved groups. Five Clinical Sequencing Evidence-Generating Research consortium studies performed GS in children with suspected genetic conditions with high proportions of individuals from underserved groups to address this evidence gap.</div></div><div><h3>Methods</h3><div>Parents completed surveys of perceived understanding, personal utility, and test-related distress after GS result disclosure. We assessed outcomes’ associations with child- and parent-related factors: child age; type of GS finding; and parent health literacy, numeracy, and education.</div></div><div><h3>Results</h3><div>A total of 1763 parents completed surveys; 83% met “underserved” criteria based on race, ethnicity, and risk factors for barriers to access. We observed high perceived understanding and personal utility and low test-related distress. Outcomes were associated with the type of GS finding; parents of children with a pathogenic or likely pathogenic finding endorsed higher personal utility and more test-related distress than those whose children had a variant of uncertain significance or normal finding. Personal utility was higher in parents who met the criteria for “underserved.”</div></div><div><h3>Conclusion</h3><div>Our findings shed light on correlates of parents’ cognitive and emotional responses to their child’s GS findings and emphasize the need for tailored support in disclosure discussions.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101363"},"PeriodicalIF":6.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023197","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":"Longitudinal outcomes in Noonan syndrome","authors":"Alyssa L. Rippert ,&nbsp;Rebecca Reef ,&nbsp;Ashika Mani ,&nbsp;Arianna K. Stefanatos ,&nbsp;Rebecca C. Ahrens-Nicklas","doi":"10.1016/j.gim.2025.101355","DOIUrl":"10.1016/j.gim.2025.101355","url":null,"abstract":"<div><h3>Purpose</h3><div>Noonan syndrome and related disorders (NS) are multisystemic conditions affecting approximately 1:1000 individuals. Previous natural history studies were conducted before widespread comprehensive genetic testing. This study provides updated longitudinal natural history data in participants with molecularly confirmed NS.</div></div><div><h3>Methods</h3><div>Comprehensive medical, developmental, and health care utilization (HCU) data were abstracted from the medical records of participants with molecularly confirmed NS. Primary outcomes included developmental outcomes, classroom setting, and HCU.</div></div><div><h3>Results</h3><div>A total of 172 patients with molecularly confirmed NS were followed for 1142.2 patient-years total. An average of 3.7 affected organ systems on initial evaluation. Sitting, walking, and talking in two-word phrases all occurred earlier than in previous cohorts (<em>P</em> = .003, <em>P</em> = .001, and <em>P</em> &lt; .0001, respectively). Genotype influenced the age at milestones and classroom setting; feeding difficulties also influenced the age at milestones. HCU was significantly higher in patients with NS compared with peers (<em>P</em> &lt; .0001) and highest in infancy and adolescence.</div></div><div><h3>Conclusion</h3><div>Developmental outcomes have improved compared with previous cohorts. Predictors of outcome may identify those at highest risk for developmental delay allowing for appropriate intervention. Children and adolescents with NS have an increased burden of HCU compared with their peers. Multidisciplinary care coordination is needed to decrease medical burden and improve health of patients and families.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101355"},"PeriodicalIF":6.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978273","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":"The impact of genetic counselor involvement in genetic and genomic test order review: A scoping review","authors":"Courtney B. Cook ,&nbsp;Carly Pistawka ,&nbsp;Alison M. Elliott","doi":"10.1016/j.gim.2025.101354","DOIUrl":"10.1016/j.gim.2025.101354","url":null,"abstract":"<div><h3>Purpose</h3><div>The increasing complexity of genetic technologies paired with more genetic tests being ordered by nongenetic health care providers, has resulted in an increase in the number of inappropriately ordered tests. Genetic counselors (GCs) are ideally suited to assess the appropriateness of a genetic test.</div></div><div><h3>Methods</h3><div>We performed a scoping review of GC involvement in utilization management initiatives in order to describe the impact of having GCs involved in this process. Five databases (MEDLINE, EMBASE, CINHAL, EBM reviews, and Web of Science Core Collection) and gray literature were searched. We considered literature published in English since 2010.</div></div><div><h3>Results</h3><div>A total of 51 studies were included. The most commonly evaluated outcomes included cancellation rate, economic efficiencies, impact on medical management, diagnostic rate, and time or triage efficiencies. Several studies also described GC impact on nongenetic health care providers.</div></div><div><h3>Conclusion</h3><div>Employment of GCs in the laboratory has been implemented widely as a solution to test misordering. These studies describe ways in which GCs can be integrated into testing workflows to reduce the number of inappropriate tests and have wider impacts on nongenetic health care providers’ ordering practices and the patient experience.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101354"},"PeriodicalIF":6.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978275","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":"Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum","authors":"Daniel G. Calame ,&nbsp;Jovi Huixin Wong ,&nbsp;Puravi Panda ,&nbsp;Dat Tuan Nguyen ,&nbsp;Nancy C.P. Leong ,&nbsp;Riccardo Sangermano ,&nbsp;Sohil G. Patankar ,&nbsp;Mohamed S. Abdel-Hamid ,&nbsp;Lama AlAbdi ,&nbsp;Sylvia Safwat ,&nbsp;Kyle P. Flannery ,&nbsp;Zain Dardas ,&nbsp;Jawid M. Fatih ,&nbsp;Chaya Murali ,&nbsp;Varun Kannan ,&nbsp;Timothy E. Lotze ,&nbsp;Isabella Herman ,&nbsp;Farah Ammouri ,&nbsp;Brianna Rezich ,&nbsp;Stephanie Efthymiou ,&nbsp;Long N. Nguyen","doi":"10.1016/j.gim.2024.101273","DOIUrl":"10.1016/j.gim.2024.101273","url":null,"abstract":"<div><h3>Purpose</h3><div><em>FLVCR1</em> encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although <em>Flvcr1</em>^−/− mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic <em>FLVCR1</em> variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.</div></div><div><h3>Methods</h3><div>We identified individuals with undiagnosed neurodevelopmental disorders and biallelic <em>FLVCR1</em> variants through international data sharing and characterized the functional consequences of their <em>FLVCR1</em> variants.</div></div><div><h3>Results</h3><div>We ascertained 30 patients from 23 unrelated families with biallelic <em>FLVCR1</em> variants and characterized a novel <em>FLVCR1</em>-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (<em>z</em>-score −2.5 to −10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with <em>Flvcr1</em>^−/− mice and DBA. <em>FLVCR1</em> variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.</div></div><div><h3>Conclusion</h3><div>These data demonstrate a broad <em>FLVCR1</em>-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101273"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284360","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":"Multi-ethnic heterozygote frequencies of cancer susceptibility genes to inform counseling of reproductive risk","authors":"Jacquelyn Powers ,&nbsp;Heather Wachtel ,&nbsp;Erica Trujillo ,&nbsp;Heena Desai ,&nbsp;Ryan Hausler ,&nbsp;Laura Conway ,&nbsp;Bradley Wubbenhorst","doi":"10.1016/j.gim.2024.101246","DOIUrl":"10.1016/j.gim.2024.101246","url":null,"abstract":"<div><h3>Purpose</h3><div>Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited.</div></div><div><h3>Methods</h3><div>Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (<em>ATM</em>, <em>BRCA1</em>, <em>BRCA2</em>, <em>BRIP1</em>, <em>FH</em>, <em>NBN</em>, <em>MLH1</em>, <em>MSH2</em>, <em>MSH6</em>, <em>PMS2</em>, <em>RAD51C</em>, <em>SDHA</em>, <em>SDHB</em>, and <em>SDHD</em>) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES.</div></div><div><h3>Results</h3><div>Average frequencies of heterozygotes with PGVs across ancestries for <em>BRCA1</em> and <em>BRCA2</em> were 0.33% ± 0.41% and 0.43% ± 0.36%, with variability cross-ancestry from 0.06% to 1.32% and 0.17% to 1.29%, respectively. <em>ATM</em> had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and <em>SDHD</em> the lowest (0.01% ± 0.01%) average PGV heterozygote frequency. Heterozygote PGV frequencies from gnomAD were similar as cancer-free individuals in Penn Medicine Biobank and higher than in the FLOSSIES data.</div></div><div><h3>Discussion</h3><div>Heterozygote frequency estimates for AD CPGs that cause AR disease provides information to facilitate discussions regarding reproductive risk. Future studies are needed to assess whether utilization of these data will influence couples’ reproductive risk planning.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101246"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681571","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 factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic","authors":"Nicole R. Wong ,&nbsp;Alexandra Klomhaus ,&nbsp;David J. Adams ,&nbsp;Benjamin N. Schneider ,&nbsp;Sunil Mehta ,&nbsp;Charlotte DiStefano ,&nbsp;Rujuta B. Wilson ,&nbsp;Julian A. Martinez-Agosto ,&nbsp;Shafali S. Jeste ,&nbsp;Aaron D. Besterman","doi":"10.1016/j.gim.2024.101252","DOIUrl":"10.1016/j.gim.2024.101252","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.</div></div><div><h3>Results</h3><div>Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101252"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463191","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}