Genetics in Medicine最新文献

{"title":"Trends in and predictors of patient pharmacogenomic test uptake in a national health care system","authors":"Abigail Silva ,&nbsp;Deepak Voora ,&nbsp;Rebekah Ryanne Wu ,&nbsp;Brian Bartle ,&nbsp;Catherine Chanfreau-Coffinier ,&nbsp;Allison Hung ,&nbsp;Corrine I. Voils","doi":"10.1016/j.gim.2024.101308","DOIUrl":"10.1016/j.gim.2024.101308","url":null,"abstract":"<div><h3>Purpose</h3><div>Better understanding patient uptake of pharmacogenomic (PGx) testing may inform its implementation and maximize the benefits that such testing can confer. This study examined patient and provider factors associated with PGx test ordering in a national health care system in which panel-based testing was implemented as part of routine care.</div></div><div><h3>Methods</h3><div>We used a retrospective matched cohort design and data from the Veterans Health Administration Corporate Data Warehouse. A conditional logistic model was used to identify factors associated with a PGx order receipt and estimate odds ratios and 95% confidence intervals.</div></div><div><h3>Results</h3><div>The following patient factors predicted receipt of a PGx test order: younger age, married status, rural residence, non-Hispanic Black or Hispanic race/ethnicity, PGx educational mailer receipt, depression diagnosis, allergy to a drug on the panel, prescriptions for drugs on the panel, and specialty care visits (<em>P &lt; .</em>05). Additionally, patients whose providers were female, younger, a nurse practitioner/physician assistant or pharmacist, or participated in an educational mailer program were more likely to receive an order (<em>P &lt; .</em>05).</div></div><div><h3>Conclusion</h3><div>This study highlights factors that may facilitate or hinder the widespread and equitable implementation of PGx testing in a large national health care system. The information is being used to further refine the program.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101308"},"PeriodicalIF":6.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557768","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":"The Clinician-reported Genetic Testing Utility Index (C-GUIDE) for Prenatal Care: Initial evidence of content and construct validity","authors":"Robin Z. Hayeems ,&nbsp;Stephanie Luca ,&nbsp;Bowen Xiao ,&nbsp;Christie Boswell-Patterson ,&nbsp;Carolina Lavin Venegas ,&nbsp;Clarissa R. Abi Semaan ,&nbsp;Tessa Kolar ,&nbsp;Diane Myles-Reid ,&nbsp;Lauren Chad ,&nbsp;David Dyment ,&nbsp;Kym M. Boycott ,&nbsp;Joanna Lazier ,&nbsp;Wendy J. Ungar ,&nbsp;Christine M. Armour","doi":"10.1016/j.gim.2024.101306","DOIUrl":"10.1016/j.gim.2024.101306","url":null,"abstract":"<div><h3>Purpose</h3><div>To develop and assess the face and construct validity of the Clinician-reported Genetic Testing Utility Index (C-GUIDE) for genetic testing in prenatal care.</div></div><div><h3>Methods</h3><div>After a literature review and consultation with clinical experts, a preliminary draft of C-GUIDE Prenatal was developed. Its face and content validity were then assessed by 19 prenatal genetics’ providers using interviews and surveys. Feedback informed further revisions. To test construct validity, 4 geneticist raters completed C-GUIDE on a retrospective sample of cases that received prenatal genetic testing and completed a concurrent global assessment of utility of these cases using an anchor item. A generalized estimating equations model was used to adjust for rater correlation and measure the association between C-GUIDE scores, global item scores, and potential clinical variables.</div></div><div><h3>Results</h3><div>To develop C-GUIDE Prenatal, 7 items were removed, 10 items were modified, and 4 items were added. For 101 cases rated for validation, on average, a 1-point increase in the global item score was associated with an increase of 1.1 in the C-GUIDE score (<em>P</em> = .04). Compared with uninformative results, informative positive and informative negative results were associated with a mean increase of 10.7 (SE = 1.05) (<em>P</em> &lt; .001) and 5.6 (SE = 1.85) (<em>P</em> &lt; .001), respectively. As indications for testing, known/familial variants were associated with a mean increase in the C-GUIDE score of 4.7 (SE = 2.21) (<em>P</em> &lt; .001) compared with ultrasound findings. C-GUIDE scores increased by a mean of 3.0 (SE = 0.23) among cases for whom pregnancies were ongoing compared with those for whom they were not (<em>P</em> &lt; .01).</div></div><div><h3>Conclusion</h3><div>The significant positive associations between C-GUIDE total and the global item score and between C-GUIDE total, result type, indication for testing, and pregnancy status in the expected directions provide evidence of construct validity.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101306"},"PeriodicalIF":6.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567301","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":"Impact of early diagnosis, disease variant, and quality of care on the neurocognitive outcome in maple syrup urine disease: A meta-analysis","authors":"Svenja Scharre,&nbsp;Katharina Mengler,&nbsp;Elena Schnabel,&nbsp;Oya Kuseyri Hübschmann,&nbsp;Ali Tunç Tuncel,&nbsp;Georg Friedrich Hoffmann,&nbsp;Sven F. Garbade,&nbsp;Ulrike Mütze,&nbsp;Stefan Kölker","doi":"10.1016/j.gim.2024.101303","DOIUrl":"10.1016/j.gim.2024.101303","url":null,"abstract":"<div><h3>Purpose</h3><div>Maple syrup urine disease (MSUD) is a rare inherited metabolic disease characterized by recurrent metabolic decompensations, neurocognitive impairment, and limited life expectancy. This meta-analysis aims to evaluate the impact of early diagnosis by newborn screening (NBS) on mortality and neurocognitive outcome in survivors, taking into account the quality of national health care systems.</div></div><div><h3>Methods</h3><div>Systematic literature search was performed according to Preferred Reporting Items for Systematic Review and Meta-Analysis protocol. Effects on outcome parameters were analyzed using meta-analytical measures and reanalysis of individual participant data.</div></div><div><h3>Results</h3><div>Thirty-three studies were included, reporting on 1141 individuals with MSUD. Participants with classic MSUD presented a more severe phenotype compared with variant MSUD as demonstrated by higher mortality rate (17.1% versus 0%), and lower median IQ (90 versus 104; <em>P</em> &lt; .001, linear mixed model). NBS was associated with improved cognition (mean IQ: 95 versus 82; <em>P</em> = .014, random effects model) and decreased mortality (3% versus 14.6%; <em>P</em> = .028, Kaplan-Meier estimates) compared with individuals identified after onset of symptoms, in trend even after the exclusion of individuals with variant MSUD. Quality of national health care systems correlated with survival (<em>P =</em> .025, meta-regression) and permanent neurological symptoms (<em>P =</em> .031, meta-regression).</div></div><div><h3>Conclusion</h3><div>NBS is a prerequisite to improved outcome in individuals with MSUD; however, health benefit critically depends on the quality of the national health care systems.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101303"},"PeriodicalIF":6.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463207","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":"Leveraging clinical intuition to improve accuracy of phenotype-driven prioritization","authors":"Martha A. Beckwith ,&nbsp;Daniel Danis ,&nbsp;Yasemin Bridges ,&nbsp;Julius O.B. Jacobsen ,&nbsp;Damian Smedley ,&nbsp;Peter N. Robinson","doi":"10.1016/j.gim.2024.101292","DOIUrl":"10.1016/j.gim.2024.101292","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>The LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) algorithm calculates the likelihood ratio of clinical manifestations represented by Human Phenotype Ontology 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.</div></div><div><h3>Results</h3><div>The average rank of the correct diagnosis in simulations using ClintLR showed a statistically significant improvement over a range of adjustment factors.</div></div><div><h3>Conclusion</h3><div>ClintLR successfully encodes clinical intuition to improve ranking of rare diseases in diagnostic sequencing. ClintLR is freely available at <span><span>https://github.com/TheJacksonLaboratory/ClintLR</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101292"},"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":"OA","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 ,&nbsp;Anderson Rodrigues Brandão Paiva ,&nbsp;Antonio Duarte Amorim Junior ,&nbsp;Pedro Lucas Grangeiro Sá Barreto Lima ,&nbsp;Katiane Sayão Souza Cabral ,&nbsp;Isabella Peixoto Barcelos ,&nbsp;André Luis Santos Pessoa ,&nbsp;Carlos Frederico Leite Souza-Lima ,&nbsp;Matheus Augusto Araújo Castro ,&nbsp;Fernando Freua ,&nbsp;Emerson de Santana Santos ,&nbsp;Margleice Marinho Vieira Rocha ,&nbsp;Rayana Elias Maia ,&nbsp;Rodrigo Santos Araújo ,&nbsp;Juan David Guevara Ramos ,&nbsp;Rosane Guazi Resende ,&nbsp;Gerson da Silva Carvalho ,&nbsp;Luciana Patrizia Andrade Valença ,&nbsp;José Ronaldo Lima de Carvalho Jr. ,&nbsp;Eduardo Sousa Melo ,&nbsp;David S. Lynch","doi":"10.1016/j.gim.2024.101291","DOIUrl":"10.1016/j.gim.2024.101291","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>This was a retrospective observational study including patients with CLN11. Patients were identified through an active search for granulin precursor gene (<em>GRN</em>) 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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101291"},"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":"OA","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":"Heidi L. Cope ,&nbsp;Laura V. Milko ,&nbsp;Elizabeth R. Jalazo ,&nbsp;Blythe G. Crissman ,&nbsp;Ann Katherine M. Foreman ,&nbsp;Bradford C. Powell ,&nbsp;Neal A. deJong ,&nbsp;Jessica Ezzell Hunter ,&nbsp;Beth Lincoln Boyea ,&nbsp;Ana N. Forsythe ,&nbsp;Anne C. Wheeler ,&nbsp;Rebekah S. Zimmerman ,&nbsp;Sharon F. Suchy ,&nbsp;Amber Begtrup ,&nbsp;Katherine G. Langley ,&nbsp;Kristin G. Monaghan ,&nbsp;Christina Kraczkowski ,&nbsp;Kathleen S. Hruska ,&nbsp;Paul Kruszka ,&nbsp;Katerina S. Kucera ,&nbsp;Holly L. Peay","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":"26 12","pages":"Article 101290"},"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":"Hsiang-Yu Lin ,&nbsp;Chung-Lin Lee ,&nbsp;Ya-Hui Chang ,&nbsp;Yuan-Rong Tu ,&nbsp;Yun-Ting Lo ,&nbsp;Jun-Yi Wu ,&nbsp;Dau-Ming Niu ,&nbsp;Mei-Ying Liu ,&nbsp;Hsin-Yun Liu ,&nbsp;Hsiao-Jan Chen ,&nbsp;Shu-Min Kao ,&nbsp;Li-Yun Wang ,&nbsp;Huey-Jane Ho ,&nbsp;Chih-Kuang Chuang ,&nbsp;Shuan-Pei Lin","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":"26 12","pages":"Article 101286"},"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 ,&nbsp;Leora Witkowski ,&nbsp;Afrida Ahmed ,&nbsp;Charlie F. Rowlands ,&nbsp;Susana Banerjee ,&nbsp;Joseph G. Pressey ,&nbsp;Terri P. McVeigh ,&nbsp;Marc D. Tischkowitz ,&nbsp;William D. Foulkes ,&nbsp;Clare Turnbull ,&nbsp;SCCOHT-SMARCA4 Registry Consortium","doi":"10.1016/j.gim.2024.101287","DOIUrl":"10.1016/j.gim.2024.101287","url":null,"abstract":"<div><h3>Purpose</h3><div>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 <em>SMARCA4</em>. Early bilateral oophorectomy is recommended for unaffected females with a <em>SMARCA4</em> GPV. However, the penetrance of <em>SMARCA4</em> GPVs for SCCOHT is highly uncertain and subject to ascertainment bias.</div></div><div><h3>Methods</h3><div>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 <em>SMARCA4</em> GPVs in females compared with males in UK Biobank, a population cohort for which recruitment was restricted to those age 40 to 69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry.</div></div><div><h3>Results</h3><div>We observed <em>SMARCA4</em> GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (<em>P</em> = .028), representing a male:female odds ratio of 2.64 (95% CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given the absence of other <em>SMARCA4</em>-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for <em>BRCA1</em> and <em>TP53</em>.</div></div><div><h3>Conclusion</h3><div>Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with <em>SMARCA4</em> GPVs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101287"},"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":"Irene Valenzuela ,&nbsp;Marta Codina-Solà ,&nbsp;Elida Vazquez ,&nbsp;Anna Cueto-González ,&nbsp;Jordi Leno-Colorado ,&nbsp;Amaia Lasa-Aranzasti ,&nbsp;Laura Trujillano ,&nbsp;Bárbara Masotto ,&nbsp;Miriam Masas ,&nbsp;Mar Escobar ,&nbsp;Elena García-Arumí ,&nbsp;Eduardo F. Tizzano","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":"26 12","pages":"Article 101288"},"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":"26 10","pages":"Article 101208"},"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}