Genetics in Medicine最新文献

{"title":"Critically unwell infants and children with mitochondrial disorders diagnosed by ultra-rapid genomic sequencing.","authors":"Megan Ball, Sophie E Bouffler, Christopher B Barnett, Mary-Louise Freckmann, Matthew F Hunter, Benjamin Kamien, Karin S Kassahn, Sebastian Lunke, Chirag V Patel, Jason Pinner, Tony Roscioli, Sarah A Sandaradura, Hamish S Scott, Tiong Y Tan, Mathew Wallis, Alison G Compton, David R Thorburn, Zornitza Stark, John Christodoulou","doi":"10.1016/j.gim.2024.101293","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101293","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultra-rapid genomic testing as part of a national program.</p><p><strong>Methods: </strong>Ultra-rapid genomic sequencing was performed in 454 families (genome sequencing: n=290, exome sequencing +/- mitochondrial DNA sequencing: n=164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.</p><p><strong>Results: </strong>A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD following broader analysis. Gene-agnostic analysis led to the discovery of two novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another four individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.</p><p><strong>Conclusion: </strong>Ultra-rapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463205","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, Alexandra Klomhaus, David J Adams, Benjamin N Schneider, Sunil Mehta, Charlotte DiStefano, Rujuta B Wilson, Julian A Martinez-Agosto, Shafali S Jeste, Aaron D Besterman","doi":"10.1016/j.gim.2024.101252","DOIUrl":"10.1016/j.gim.2024.101252","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Clinical Intuition to Improve Accuracy of Phenotype-Driven Prioritization.","authors":"Martha A Beckwith, Daniel Danis, Yasemin Bridges, Julius O B Jacobsen, Damian Smedley, Peter N Robinson","doi":"10.1016/j.gim.2024.101292","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101292","url":null,"abstract":"<p><strong>Purpose: </strong>Clinical intuition is commonly incorporated into the differential diagnosis as an assessment of the likelihood of candidate diagnoses based either on the patient population being seen in a specific clinic or on the signs and symptoms of the initial presentation. Algorithms to support diagnostic sequencing in individuals with a suspected rare genetic disease do not yet incorporate intuition and instead assume that each Mendelian disease has an equal pretest probability.</p><p><strong>Methods: </strong>The LIRICAL algorithm calculates the likelihood ratio of clinical manifestations represented by Human Phenotype Ontology (HPO) terms to rank candidate diagnoses. The initial version of LIRICAL assumed an equal pretest probability for each disease in its calculation of the posttest probability (where the test is diagnostic exome or genome sequencing). We introduce Clinical Intuition for Likelihood Ratios (ClintLR), an extension of the LIRICAL algorithm that boosts the pretest probability of groups of related diseases deemed to be more likely.</p><p><strong>Results: </strong>The average rank of the correct diagnosis in simulations using ClintLR showed a statistically significant improvement over a range of adjustment factors.</p><p><strong>Conclusion: </strong>ClintLR successfully encodes clinical intuition to improve ranking of rare diseases in diagnostic sequencing. ClintLR is freely available at https://github.com/TheJacksonLaboratory/ClintLR.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463208","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":"Further description of the phenotypic spectrum of neuronal ceroid lipofuscinosis type 11.","authors":"Paulo Ribeiro Nóbrega, Anderson Rodrigues Brandão Paiva, Antonio Duarte Amorim Junior, Pedro Lucas Grangeiro Sá Barreto Lima, Katiane Sayão Souza Cabral, Isabella Peixoto Barcelos, André Luis Santos Pessoa, Carlos Frederico Leite Souza-Lima, Matheus Augusto Araújo Castro, Fernando Freua, Emerson de Santana Santos, Margleice Marinho Vieira Rocha, Rayana Elias Maia, Rodrigo Santos Araújo, Juan David Guevara Ramos, Rosane Guazi Resende, Gerson da Silva Carvalho, Luciana Patrizia Andrade Valença, José Ronaldo Lima de Carvalho, Eduardo Sousa Melo, José Luiz Pedroso, Orlando Graziani Povoas Barsottini, Henry Houlden, Fernando Kok, David S Lynch","doi":"10.1016/j.gim.2024.101291","DOIUrl":"10.1016/j.gim.2024.101291","url":null,"abstract":"<p><strong>Purpose: </strong>Ceroid lipofuscinosis type 11 (CLN11) is a very rare disease, being reported in only 13 unrelated families so far. Further reports are necessary to comprehend the clinical phenotype of this condition. This article aims to report 9 additional cases of CLN11 from 9 unrelated Latin American families presenting with relatively slow disease progression.</p><p><strong>Methods: </strong>This was a retrospective observational study including patients with CLN11. Patients were identified through an active search for granulin precursor gene (GRN) pathogenic variants across the entire database of next-generation sequencing of a commercial laboratory and by contacting attending physicians to check for clinical and radiologic findings compatible with a neuronal ceroid lipofuscinosis phenotype.</p><p><strong>Results: </strong>Nine CLN11 patients from unrelated families were evaluated. Age of onset varied between 3 to 17 years. The most common findings were visual impairment, cerebellar ataxia, seizures, myoclonus, and cognitive decline. One patient had a previously unreported finding of cervical, perioral, and tongue myoclonus. Most of the patients were able to walk unassisted after an average of 14.2 years (SD 4.76 y) from disease onset.</p><p><strong>Conclusion: </strong>We describe 9 new cases of a very rare type of neuronal ceroid lipofuscinosis (CLN11) from Latin America with a recurrent p.(Gln257ProfsTer27) and a novel p.(Cys83Ter) nonsense variant. Our findings suggest that a slowly progressive neuronal ceroid lipofuscinosis might be a clue for the diagnosis of CLN11.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463206","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":"A systematic framework for selecting gene-condition pairs for inclusion in newborn sequencing panels: Early Check implementation","authors":"","doi":"10.1016/j.gim.2024.101290","DOIUrl":"10.1016/j.gim.2024.101290","url":null,"abstract":"<div><h3>Purpose</h3><div>Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies.</div></div><div><h3>Methods</h3><div>Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (panel 1-high actionability, panel 2-possible actionability). A previously developed framework, the Age-based Semi Quantitative Metric (ASQM), was adapted. Increasing ASQM scores, with a maximum of 15, suggest greater actionability. Wilcoxon tests were performed to compare panel 1 gene-condition pairs on the Recommended Uniform Screening Panel (RUSP) with non-RUSP pairs.</div></div><div><h3>Results</h3><div>In our first round of assessment<strong>,</strong> Early Check identified 178 gene-condition pairs for inclusion in panel 1 and 29 for panel 2. Median ASQM scores of RUSP conditions on panel 1 was 12 (range 4 to 15) and non-RUSP was 13 (range 9 to 15). Median scores for panel 2 was 10 (range 6 to 14).</div></div><div><h3>Conclusion</h3><div>The Early Check frameworks provide a transparent, semiquantitative, and reproducible methodology for selecting gene-condition pairs for newborn screening sequencing pilot studies that may inform future integration of genomic sequencing into population-level newborn screening. Collaborative efforts among newborn sequencing studies to establish shared criteria is needed to enhance cross-study comparisons.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389822","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":"Implementation of newborn screening for mucopolysaccharidosis type IVA and long-term monitoring in Taiwan","authors":"","doi":"10.1016/j.gim.2024.101286","DOIUrl":"10.1016/j.gim.2024.101286","url":null,"abstract":"<div><h3>Purpose</h3><div>Mucopolysaccharidosis IVA (MPS IVA) is a rare lysosomal storage disorder arising from a deficiency in N-acetylgalactosamine-6-sulfatase.</div></div><div><h3>Methods</h3><div>From September 2019 to October 2023, a total of 264,843 Taiwanese newborns underwent screening for MPS IVA using dried blood spots and tandem mass spectrometry.</div></div><div><h3>Results</h3><div>Among the 95 referred infants, 9 (9%) were confirmed to have MPS IVA (group 1), 18 (19%) were highly suspected to have MPS IVA (group 2), 61 (64%) were identified as heterozygotes of MPS IVA (group 3), and 7 (7%) were determined not to have MPS IVA (group 4). A total of 34 different <em>GALNS</em> (HGNC:4122) gene variants were identified through our MPS IVA newborn screening program. The most prevalent variant was c.857C&gt;T p.(Thr286Met), found in 33 cases (29%), followed by c.953T&gt;G p.(Met318Arg) in 22 cases (19%). Intravenous enzyme replacement therapy was initiated in 5 patients at ages ranging from 0.3 to 1.7 years. The estimated incidence of MPS IVA in this screening program was 3.4 per 100,000 live births.</div></div><div><h3>Conclusion</h3><div>Because of the progressive nature of MPS IVA, an early diagnosis facilitated by newborn screening and prompt initiation of enzyme replacement therapy before irreversible organ damage occurs may result in improved clinical outcomes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389823","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":"Using cancer phenotype sex-specificity to enable unbiased penetrance estimation of SMARCA4 pathogenic variants for small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).","authors":"Isaac Wade, Leora Witkowski, Afrida Ahmed, Charlie F Rowlands, Terri P McVeigh, Marc D Tischkowitz, William D Foulkes, Clare Turnbull","doi":"10.1016/j.gim.2024.101287","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101287","url":null,"abstract":"<p><strong>Purpose: </strong>Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an extremely rare, highly aggressive cancer (mean age of onset, 24 years). Nearly all cases are associated with somatic or germline pathogenic variants (GPVs) in SMARCA4. Early bilateral oophorectomy is recommended for unaffected females with a SMARCA4 GPV. However, the penetrance of SMARCA4 GPVs for SCCOHT is highly uncertain and subject to ascertainment bias.</p><p><strong>Methods: </strong>Leveraging the early-onset, sex-specific, highly morbid nature of SCCOHT, we hypothesized that the penetrance for SCCOHT could be quantified from the deficit in SMARCA4 GPVs in females compared to males in UK Biobank, a population cohort for which recruitment was restricted to those age 40-69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry.</p><p><strong>Results: </strong>We observed SMARCA4 GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (p = 0.028), representing a male:female odds ratio of 2.64 (95%CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given absence of other SMARCA4-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for BRCA1 and TP53.</p><p><strong>Conclusion: </strong>Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with SMARCA4 GPVs.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375383","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":"Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome","authors":"","doi":"10.1016/j.gim.2024.101288","DOIUrl":"10.1016/j.gim.2024.101288","url":null,"abstract":"<div><h3>Purpose</h3><div>Despite ever-increasing knowledge of the genetic etiologies of neurodevelopmental disorders, approximately half remain undiagnosed after exome or genome sequencing. Here, we provide a deep clinical characterization of 11 previously unreported patients with a recently described neurodevelopmental disorder (NDD) due to pathogenic variants in <em>RNU4-2</em>.</div></div><div><h3>Methods</h3><div>The 11 patients were identified in a pool of 70 patients selected for targeted <em>RNU4-2</em> sequencing on the basis of their clinical phenotypes from a cohort of 1032 individuals with a NDD and without a prior genetic diagnosis.</div></div><div><h3>Results</h3><div>The 11 patients were aged between 13 months and 36 years. All patients showed moderate to severe developmental delay and/or intellectual disability. Height and weight were below 10th percentile and most showed microcephaly. In almost 50% of the patients, intrauterine growth retardation was detected. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelid and epicanthus, full cheeks, tented philtrum, mouth constantly slightly open with an everted lower lip vermilion, high palate, and profuse drooling. Of 11 patients, 64% also presented with ophthalmological problems (mainly strabismus, nystagmus, and refraction errors) and 64% had musculoskeletal features (joint hypermobility, mild scoliosis, and easy fractures).</div></div><div><h3>Conclusion</h3><div>This work provides an improved characterization of the phenotypic spectrum of <em>RNU4-2</em> syndrome across different age groups and demonstrates that thorough clinical assessment of patients with an NDD can be enhanced significantly for this novel syndrome.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377758","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 “Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants” by Wermers et al","authors":"","doi":"10.1016/j.gim.2024.101208","DOIUrl":"10.1016/j.gim.2024.101208","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554698","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 providing expert witness testimony for the specialty of medical genetics: A statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"","doi":"10.1016/j.gim.2024.101229","DOIUrl":"10.1016/j.gim.2024.101229","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139952","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}