Genetics in Medicine最新文献

{"title":"Recognizing the Evolution of Clinical Syndrome Spectrum Progression in Individuals with Single Large-Scale mitochondrial DNA deletion syndromes (SLSMDS).","authors":"Rebecca Ganetzky, Katelynn D Stanley, Laura E MacMullen, Ibrahim George-Sankoh, Jing Wang, Amy Goldstein, Rui Xiao, Marni J Falk","doi":"10.1016/j.gim.2025.101386","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101386","url":null,"abstract":"<p><strong>Introduction: </strong>Single Large-Scale mtDNA Deletions (SLSMD) result in Single Large Scale Deletion Syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least three distinct clinical phenotypes, Pearson Syndrome (PS), Kearns-Sayre Syndrome (KSS), and Chronic Progressive Ophthalmoplegia (CPEO).</p><p><strong>Methods: </strong>Facilitated review of electronic medical records, manual charts, and REDCap research databases was performed to complete a retrospective natural history study of 30 SLSMDS participants in a single health system seen between 2002 and 2020. Characteristics evaluated included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient reported outcome measures of fatigue, quality of life, and overall function.</p><p><strong>Results: </strong>Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 (HGNC:7641) occurs in 96% of SLSMD subjects regardless of clinical phenotype, which tended to evolve over time. Higher blood heteroplasmy correlated with earlier age of onset. GDF-15 was elevated in all SLSMD subjects. A PS history yielded negative survival prognosis. Furthermore, increased fatigue and decreased quality of life were reported in SLSMD subjects with advancing age.</p><p><strong>Conclusion: </strong>Retrospective natural history study of SLSMDS subjects demonstrated the evolution of classically considered PS, KSS, and CPEO clinical presentations within affected individuals, which may inform future clinical trial development.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101386"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476431","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":"How do parents decide on genetic testing in pediatrics? A systematic review.","authors":"Elena Sophia Doll, Seraina Petra Lerch, Katja Maria Schmalenberger, Karla Alex, Stefan Kölker, Heiko Brennenstuhl, Stacey Pereira, Hadley Smith, Eva C Winkler, Julia Mahal, Beate Ditzen","doi":"10.1016/j.gim.2025.101390","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101390","url":null,"abstract":"<p><strong>Purpose: </strong>This systematic review aims to identify factors that influence parents' decisions regarding pediatric diagnostic and predictive genetic testing (DT/PT). Factors are integrated into a conceptual model of decision-making. Implications for genetic counseling, research, and ethics are derived.</p><p><strong>Methods: </strong>PubMed, PsychInfo, WebofScience and references of related reviews were searched for original publications between 2000 and 2023. Extracted factors were categorized into an existing model.</p><p><strong>Results: </strong>Of 5843 publications, 56 met inclusion criteria. The included studies differentiate between DT, traditional, and expanded PT and describe factors impacting parental decisions on both to have the child genetically tested and to be informed about additional findings. Factors included: 1. benefits/hopes, 2. worries/concerns, 3. values and beliefs, 4. individual circumstances, and 5. emotional states.</p><p><strong>Conclusion: </strong>Our work extends an existing empirical decision model of family decisions about genome sequencing to genetic testing in pediatrics in general, adding the categories \"individual circumstances\" and \"emotional states\". The factors can be further integrated into the Health Belief Model; the importance of emotional states is reflected in dual-process theories, such as Fuzzy Trace Theory. Research is required on emotional states, differences between DT and PT, parents' decisions about result disclosure, and dyadic variables as decision-making predictors.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101390"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482968","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":"Parents' Perceptions of the Utility of Genetic Testing in the NICU.","authors":"Katharine Press Callahan, Rebecca Mueller, Steven Joffe, Cara Skraban, Nancy Spinner, Karen Crew, Justin Clapp, David Munson, Chris Feudtner","doi":"10.1016/j.gim.2025.101393","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101393","url":null,"abstract":"<p><strong>Background and objectives: </strong>While several studies have evaluated neonatal intensive care unit (NICU) parents' perspective on the utility of genetic testing in a research context and concluded positive appraisal, some data point to more varied perceptions.</p><p><strong>Methods: </strong>We conducted semi-structured interviews to elicit NICU parents' beliefs about the ways in which clinical (non-research) genetic testing could be both helpful and harmful.</p><p><strong>Results: </strong>We interviewed 43 parents of 36 neonates who had been recommended, and either accepted or declined, clinical genetic testing. Parents described five types of problems they believed genetic information may address, what we term \"problem-solving contexts:\" treatment, coping, parenting, prognostic, and existential contexts. Most parents considered multiple problem-solving contexts in assessing benefit, frequently resulting in ambivalence.</p><p><strong>Conclusions: </strong>Parents in the NICU appear to be more ambivalent about the utility of genetic information than is reflected in most recent studies. This discrepancy is likely related to both our sample population, clinical rather than research, and our methodology, which encouraged parents to discuss contexts beyond the medical. Our findings suggest that informed pre-test consent discussions and post-test counseling should engage parents in discussing multiple problem-solving contexts. Researchers should also find ways to incorporate these multiple contexts, and diverse perspectives within each context, into utility measures.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101393"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482969","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":"ClinGen recuration of hearing loss associated-genes demonstrates significant changes in gene-disease validity over time.","authors":"Kezang C Tshering, Marina T DiStefano, Andrea M Oza, Pamela Ajuyah, Ryan Webb, Enyonam Edoh, Ellie Broeren, Julie Ratliff, Vanessa Gitau, Kelley Paris, Amal Aburyyan, John Alexander, Victoria Albano, Donglin Bai, Kevin Ta Booth, Paula I Buonfiglio, Cherine Charfeddine, Viviana Dalamón, Ignacio Del Castillo, Miguel Angel Moreno-Pelayo, Hatice Duzkale, Ben Dorshorst, Rabia Faridi, Margaret Kenna, Morag A Lewis, Minjie Luo, Yu Lu, Rahma Mkaouar, Tatsuo Matsunaga, Kiyomitsu Nara, Arti Pandya, Shelby Redfield, Isabelle Roux, Lisa A Schimmenti, Isabelle Schrauwen, Sherin Shaaban, Jun Shen, Barbara Vona, Richard J Smith, Heidi L Rehm, Hela Azaiez, Ahmad N Abou Tayoun, Sami S Amr","doi":"10.1016/j.gim.2025.101392","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101392","url":null,"abstract":"<p><strong>Purpose: </strong>The ClinGen Hearing Loss Gene Curation Expert Panel (GCEP) was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semi-quantitative framework. ClinGen mandates timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong, every 2-3 years.</p><p><strong>Methods: </strong>Thirty-five GDRs met the criteria for recuration within two years of original curation. Previous evidence was reevaluated using the latest curation guidelines and a comprehensive literature review was performed for new evidence. The recurations were approved by the GCEP and published to the ClinGen website (www.clinicalgenome.org).</p><p><strong>Results: </strong>Eight out of 35 (22%) GDRs changed classification. Two Moderate and five Strong GDRs upgraded to Definitive due to new case evidence. One Strong was subsumed under another Definitive GDR, after evaluation of lumping/splitting of disease entities. Twenty-seven out of 35 remained unchanged with little to no new evidence reported.</p><p><strong>Conclusion: </strong>Genes classified as Moderate and Strong are likely to build evidence and change in classification over time, whereas Limited are unlikely to gain evidence. These findings also highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most up-to-date evidence into their efforts.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101392"},"PeriodicalIF":6.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482967","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":"DICER1 in pediatric and adult cancer predisposition populations: prevalence, phenotypes and mosaics.","authors":"Lluis Salvador, Jesús Del Valle, Eduard Dorca, Anne-Sophie Chong, Anne-Laure Chong, José Camacho Valenzuela, Elisabet Munté, Cristina Rioja, Laura Martí-Sánchez, Mónica Salinas, Esther Darder, Marc R Fabian, Joan Brunet, Hector Salvador, Conxi Lázaro, Barbara Rivera","doi":"10.1016/j.gim.2025.101385","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101385","url":null,"abstract":"<p><strong>Purpose: </strong>DICER1 tumor predisposition syndrome (DTPS) is a hereditary condition affecting children and young adults. Identification of DICER1 carriers is key for prevention and actionability in families. However, DTPS diagnosis is hindered by its incomplete penetrance and broad phenotypic spectrum.</p><p><strong>Methods: </strong>We performed an analysis of DICER1 sequencing data from 92 children and 6108 adults with a suspected cancer predisposition syndrome. Clinical and DICER1 somatic data from selected carriers and public datasets were studied.</p><p><strong>Results: </strong>The prevalence of germline DICER1 PVs was 1:30 in children and 1:3054 in adults. No adult referral phenotype was a known DTPS-associated tumor, although 3/5 carriers developed thyroid alterations. We provide functional evidence supporting the pathogenicity of a novel in-frame deletion. A 56-year-old woman with an ovarian carcinoma and a toxic diffuse thyroid hyperplasia was found to have a postzygotic hotspot missense.</p><p><strong>Conclusions: </strong>The prevalence of DICER1 PVs in cancer predisposition populations was 5-6 times that reported in the general population. Pediatric-onset DTPS is well characterized, whereas adult carriers mainly present with thyroid abnormalities in the absence of DICER1-related family history, thus requiring accurate criteria for its identification when in constellation with other tumor types. Postzygotic hotspot missenses may exist without the expected severe phenotype.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101385"},"PeriodicalIF":6.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457534","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":"Patterns of X-linked inheritance: a new approach for the genome era.","authors":"Sanjana Basava, Charles J Billington, Laura Carrel, Leslie G Biesecker, William B Dobyns","doi":"10.1016/j.gim.2025.101384","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101384","url":null,"abstract":"<p><p>The concepts of X-linked (XL) \"dominant\" and \"recessive\" inheritance originated long before dosage compensation for X chromosome genes was understood, but now have no scientific basis. To address continuing misunderstanding of XL inheritance in humans we reviewed data on penetrance, expressivity, and X chromosome inactivation for 55 XL genes and 57 XL disorders. Our analysis demonstrated widely varying penetrance in heterozygous females and variations in the patterns of inheritance based on the degree of cell selection, severity of the phenotype in males, cell autonomous or non-cell autonomous function of the gene product, and other factors. We propose four new groups of XL disorders with variations in the pattern of inheritance and recommend that the biologically flawed concepts of XL \"dominant\" and \"recessive\" inheritance for humans and other therian mammals be retired.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101384"},"PeriodicalIF":6.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440638","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, Christina Lam, Lynne Wolfe, Andrew Edmondson, Acmg Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101328","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101328","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101328"},"PeriodicalIF":6.6,"publicationDate":"2025-02-13","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mainstreaming improved adoption of germline testing for Veterans Affairs patients with metastatic prostate cancer without exacerbating disparities.","authors":"Maren T Scheuner, Katherine J Hoggatt, Paloma Sales, Barbara Lerner, Eva Ferino, Morgan Danowski, Ning Zhang, Colin Purmal, Samuel L Washington, Michael M Goodman, Emily E Ziegler, Andrea J Stoddard, Carolyn Menendez, Tori Foote, Kerry Rowe, Gina McWhirter, Michael J Kelley","doi":"10.1016/j.gim.2025.101383","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101383","url":null,"abstract":"<p><strong>Purpose: </strong>To improve germline testing adoption for Veterans Affairs (VA) patients with metastatic prostate cancer (mPrCA), new delivery models were introduced to complement genetic consultation (traditional model); mainstreaming where oncologists perform pre/post-test activities and a hybrid model where oncologists perform informed consent and then refer to genetics. We assessed germline testing adoption by delivery model.</p><p><strong>Methods: </strong>We conducted a nationwide cohort study of mPrCA patients ascertained 5/3/2021 to 11/2/2022 with follow-up through 5/3/2023. We assessed associations between patient and facility characteristics and having or completing germline test orders using Cox proportional hazards models.</p><p><strong>Results: </strong>We identified 18,623 mPrCA patients. Average age was 73.9 years (SD, 8.3, range 35-102) with 59.6% non-Hispanic White and 28.9% non-Hispanic Black patients. The cumulative incidence of germline test orders was 13.7% over two years. Non-Hispanic Black patients were more likely than non-Hispanic White patients to have germline test orders (HR, 1.28; 95%CI, 1.15-1.41) but less likely to complete their orders (HR, 0.81; 95%CI 0.72-0.91). Compared with non-Hispanic White patients, non-Hispanic Black patients were more likely to complete orders under the traditional model (HR, 1.40; 95%CI, 111-1.76), less likely under the hybrid model (OR, 0.62; 95%CI, 0.50-0.77) with no difference under the mainstream model.</p><p><strong>Conclusions: </strong>Mainstreaming germline testing for mPrCA patients improved adoption without introducing disparities between non-Hispanic Black and White patients.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101383"},"PeriodicalIF":6.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440636","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":"AUTS2-related Syndrome: Insights from a large European cohort.","authors":"Lorenzo Loberti, Loredaria Adamo, Enrica Antolini, Giulia Casamassima, Anne Destrèe, Nicola Brunetti-Pierri, David Genevieve, Philippe Christophe, Christine Coubes, Hilde Van Esch, Theresia Herget, Fanny Kortüm, Jasmin Lisfeld, Anna Charlotte Möllring, Martin Zenker, Jonathan Levy, Laurence Perrin, Anne-Claude Tabet, Anna Maruani, Arthur Sorlin, Daniel Stieber, Lucas Herissant, Karin Dahan, Lorenzo Sinibaldi, Rossella Capolino, Maria Lisa Dentici, Bruno Dallapiccola, Antonio Novelli, Livia Garavelli, Stefano Giuseppe Caraffi, Gianluca Piatelli, Irene Valenzuela, Maria Cristina Digilio, Roseline Caumes, Cordula Knopp, Karolina Chwiałkowska, Aleksandra Jezela-Stanek, Miroslaw Kwasniewski, Urszula Korotko, Ewelina Gorzałczyńska, Roberto Canitano, Salvatore Grosso, Elisa Rahikkala, Larissa Mattern, Miriam Elbracht, Orsetta Zuffardi, Valentina Caputo, Benedetta Toschi, Gea Beunders, Lisette Leeuwen, Mariet W Elting, Liselot van der Laan, Marjoleine F Broekema, Alexander J Groffen, Jiddeke M van de Kamp, Mieke M van Haelst, Marielle Alders, Salvatore Pietro Mauro, Francesca De Razza, Dora Varvara, Johanna Kick, Harald Gaspar, Dominique Braun, Eva Lausberg, Andrea Maier, Valentin Ruault, Rita Genesio, Marco Tartaglia, Rossella Tita, Mirella Bruttini, Ilaria Longo, Margherita Baldassarri, Maria Antonietta Mencarelli, Alessandra Renieri, Anna Maria Pinto","doi":"10.1016/j.gim.2025.101375","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101375","url":null,"abstract":"<p><strong>Purpose: </strong>AUTS2-related syndrome is a condition characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters AUTS2 encodes two distinct long and short isoforms encoding a putative transcriptional activator.</p><p><strong>Methods: </strong>Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2- related syndrome cohort of 58 patients harboring genomic rearrangements or single nucleotide variants (SNVs).</p><p><strong>Results: </strong>Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent from the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties and speech delay are common features of AUTS2- related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both the longer and the shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, micro-retrognathia, broad nasal base and anteverted nares. Behavioral disorders were statistically more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only noticed in patients with SNVs.</p><p><strong>Conclusion: </strong>This study provides a comprehensive clinical characterization of AUTS2- related syndrome, unravels few genotype-phenotype correlations and it suggests that disruption of the two distinct AUTS2 transcripts has a different impact on clinical phenotype.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101375"},"PeriodicalIF":6.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425271","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":"Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing.","authors":"Marissa W Mitchel, Matthew Oetjens, Alexander S F Berry, Alicia Johns, Andrés Moreno-De-Luca, Rebecca I Torene, Natasha T Strande, Marina T DiStefano, Lindsay Havens Dyer, Tracy Brandt, Brenda M Finucane, David H Ledbetter, Kyle Retterer, Christa L Martin, Scott M Myers","doi":"10.1016/j.gim.2025.101374","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101374","url":null,"abstract":"<p><strong>Purpose: </strong>Prior studies investigating the genetic architecture of pediatric motor speech disorders (MSDs) have been limited by small sample sizes and an exclusive focus on apraxia. We aimed to identify pathogenic genomic variants associated with MSDs in a large pediatric population referred for exome sequencing (ES).</p><p><strong>Methods: </strong>We identified pediatric patients with MSDs who had clinical ES between 2012-2022. The rate of pathogenic/likely pathogenic (P/LP) findings considered causative of the MSD phenotype was determined and delineated by sex and neurodevelopmental comorbidity. Gene-based burden testing compared the rate of P/LP variants in each gene in MSD cases vs. a comparison clinical ES cohort.</p><p><strong>Results: </strong>Positive diagnostic results were detected in 527 of 2004 (26.3%) patients with MSDs, with higher diagnostic rates for females and for individuals with neurodevelopmental comorbidities. P/LP sequence variants were detected in 262 genes. Gene-based, case-referent burden analysis revealed that 30 genes were nominally associated with MSDs, two of which (SETBP1, ADCY5) survived exome-wide correction.</p><p><strong>Conclusion: </strong>Over 25% of patients with MSDs were found to harbor P/LP variants in 262 genes, many of which have not previously been associated with MSDs. Potential clinical implications include early implementation of intensive speech therapy for children diagnosed with monogenic causes of MSDs.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101374"},"PeriodicalIF":6.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390719","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}