Genetics in Medicine最新文献

{"title":"Parents' experiences with sequencing of all known pediatric cancer predisposition genes in children with cancer","authors":"S.B.B. Bon ,&nbsp;R.H.P. Wouters ,&nbsp;J.J. Bakhuizen ,&nbsp;M.M. van den Heuvel-Eibrink ,&nbsp;H. Maurice-Stam ,&nbsp;M.C.J. Jongmans ,&nbsp;M.A. Grootenhuis","doi":"10.1016/j.gim.2024.101250","DOIUrl":"10.1016/j.gim.2024.101250","url":null,"abstract":"<div><h3>Purpose</h3><div>Germline DNA sequencing is increasingly used within pediatric oncology, yet parental experiences remain underexplored.</div></div><div><h3>Methods</h3><div>Parents of children undergoing cancer predisposition gene panel sequencing (143 genes) were surveyed before and after disclosure of results. Questionnaires assessed knowledge, expectations, worries, satisfaction, and regret. Next to descriptives, linear mixed models and generalized mixed models were utilized to explore factors associated with knowledge and worries.</div></div><div><h3>Results</h3><div>Out of 325 eligible families, 310 parents (176 mothers and 128 fathers of 188 families) completed all after-consent questionnaires, whereas 260 parents (150 mothers and 110 fathers of 181 families) completed all after disclosure questionnaires. Most parents hoped their participation would benefit others, although individual hopes were also common. Sequencing-related worries were common, particularly concerning whether their child would get cancer again, cancer risks for family members and psychosocial implications of testing. Parental satisfaction after disclosure was high and regret scores were low. Lower education was associated with lower knowledge levels, whereas foreign-born parents were at increased risk of experiencing worries.</div></div><div><h3>Conclusion</h3><div>Germline sequencing of children with cancer is generally well received by their parents. However, careful genetic counseling is essential to ensure that parents are adequately informed and supported throughout the process.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101250"},"PeriodicalIF":6.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145551","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":"Fraud in genetic testing: Swindling the system","authors":"Rachel Notestine ,&nbsp;Claire N. Singletary ,&nbsp;Meagan Choates ,&nbsp;Stephanie Gandomi ,&nbsp;Molly Daniels ,&nbsp;Rebecca Lunstroth ,&nbsp;Quinn Stein","doi":"10.1016/j.gim.2024.101248","DOIUrl":"10.1016/j.gim.2024.101248","url":null,"abstract":"<div><h3>Purpose</h3><div>Health care fraud comprises a sizable portion of United States health care expenditure and inflicts undue burden on payors, patients, and the health care system overall. The genetic testing industry is rapidly growing, which propagates opportunities for health care fraud. Although federal organizations have highlighted it as an issue, there is limited research exploring genetic testing fraud.</div></div><div><h3>Methods</h3><div>A retrospective review of federal websites, news articles, and a legal database resulted in 42 cases of fraud involving outpatient genetic testing published between February 2019 and December 2023. These cases were analyzed for themes via inductive conventional content analysis.</div></div><div><h3>Results</h3><div>Themes of fraudulent activity included submission of fraudulent claims, kickback or bribe payments, minimal or no contact with patients for whom testing was ordered, inappropriate billing and documentation practices, and further actions to conceal fraud. Repercussions imposed on defendants included monetary penalty, imprisonment, business restrictions, and seizure of property.</div></div><div><h3>Conclusion</h3><div>High rates of medically inappropriate testing in fraud cases highlight the value of genetics experts in ordering or reviewing claims for genetic testing. Examining fraudulent activity in genetic testing can help providers identify and report fraud and provide awareness of optimal health care allocation in the genetic testing industry.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101248"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145549","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 “The Clinical Geneticist Workforce: Community Forums to Address Challenges and Opportunities” by Chung et al","authors":"Jennifer Micham ,&nbsp;Marshall Summar ,&nbsp;Debra Regier ,&nbsp;Colleen Lawrence ,&nbsp;Deepika Burkardt","doi":"10.1016/j.gim.2024.101247","DOIUrl":"10.1016/j.gim.2024.101247","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101247"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145548","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":"Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants","authors":"Jenny Lord ,&nbsp;Carolina J. Oquendo ,&nbsp;Htoo A. Wai ,&nbsp;John G. Holloway ,&nbsp;Alexandra Martin-Geary ,&nbsp;Alexander J.M. Blakes ,&nbsp;Elena Arciero ,&nbsp;Silvia Domcke ,&nbsp;Anne-Marie Childs ,&nbsp;Karen Low ,&nbsp;Julia Rankin ,&nbsp;Genomics England Research Consortium,&nbsp;Diana Baralle ,&nbsp;Hilary C. Martin ,&nbsp;Nicola Whiffin","doi":"10.1016/j.gim.2024.101249","DOIUrl":"10.1016/j.gim.2024.101249","url":null,"abstract":"<div><h3>Purpose</h3><div>Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding “second hits” in <em>trans</em> with these is unknown.</div></div><div><h3>Methods</h3><div>In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.</div></div><div><h3>Results</h3><div>We identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in <em>GAA</em>, <em>NPHP3</em>, and <em>PKHD1</em>) and candidate diagnoses in a further 3 (<em>PAH, LAMA2,</em> and <em>IGHMBP2)</em>.</div></div><div><h3>Conclusion</h3><div>We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101249"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145550","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 frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort","authors":"Jessica Dawson ,&nbsp;Chris Kay ,&nbsp;Hailey Findlay Black ,&nbsp;Stephanie Bortnick ,&nbsp;Kyla Javier ,&nbsp;Qingwen Xia ,&nbsp;Akshdeep Sandhu ,&nbsp;Christina Buchanan ,&nbsp;Virginia Hogg ,&nbsp;Florence C.F. Chang ,&nbsp;Jun Goto ,&nbsp;Larissa Arning ,&nbsp;Carsten Saft ,&nbsp;Emilia K. Bijlsma ,&nbsp;Huu P. Nguyen ,&nbsp;Richard Roxburgh ,&nbsp;Michael R. Hayden","doi":"10.1016/j.gim.2024.101239","DOIUrl":"10.1016/j.gim.2024.101239","url":null,"abstract":"<div><h3>Purpose</h3><p>To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the <em>HTT</em> CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).</p></div><div><h3>Methods</h3><p>We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range.</p></div><div><h3>Results</h3><p>Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range.</p></div><div><h3>Conclusion</h3><p>Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse <em>HTT</em> CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101239"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024001734/pdfft?md5=1abcca0080b367715dc410d73f51671a&pid=1-s2.0-S1098360024001734-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975528","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":"Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for adult screening","authors":"Hadley Stevens Smith ,&nbsp;Caryn Kseniya Rubanovich ,&nbsp;Jill Oliver Robinson ,&nbsp;Ariel N. Levchenko ,&nbsp;Sarah A. Classen ,&nbsp;Janet Malek ,&nbsp;Adam H. Buchanan ,&nbsp;Barbara Biesecker ,&nbsp;Kyle B. Brothers ,&nbsp;Benjamin S. Wilfond ,&nbsp;Christine Rini ,&nbsp;Cinnamon S. Bloss ,&nbsp;Amy L. McGuire ,&nbsp;Sara J. Knight","doi":"10.1016/j.gim.2024.101240","DOIUrl":"10.1016/j.gim.2024.101240","url":null,"abstract":"<div><h3>Purpose</h3><p>As population-based screening programs to identify genetic conditions in adults using genomic sequencing (GS) are increasingly available, validated patient-centered outcome measures are needed to understand participants’ experience. We aimed to develop and validate an instrument to assess the perceived utility of GS in the context of adult screening.</p></div><div><h3>Methods</h3><p>Informed by a 5-domain conceptual model, we used a 5-step approach to instrument development and validation: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Adults undergoing risk-based or population-based GS who had received GS results as part of ongoing research studies participated in structured cognitive interviews and 2 rounds of surveys. After item pool refinement, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments.</p></div><div><h3>Results</h3><p>We derived the 18-item Adult Screening version of the GENEtic Utility scale (total sum score α = .87). Mirroring the Pediatric Diagnostic version, the instrument has a 2-factor structure, including an Informational Utility subscale (14 items, <span><math><mrow><mi>α</mi></mrow></math></span> = .89) and an Emotional Utility subscale (4 items, <span><math><mrow><mi>α</mi></mrow></math></span> = .75). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS. Correlations of the Emotional Utility subscale with psychosocial impact and anxiety and depression were weak to moderate.</p></div><div><h3>Conclusion</h3><p>Initial psychometric testing of the Adult Screening GENEtic Utility scale demonstrates its promise, and additional validation in translational genomics research is warranted.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101240"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975527","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":"Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules","authors":"Gioia Mastromoro ,&nbsp;Claudia Santoro ,&nbsp;Marialetizia Motta ,&nbsp;Ugo Sorrentino ,&nbsp;Paola Daniele ,&nbsp;Cristina Peduto ,&nbsp;Francesco Petrizzelli ,&nbsp;Martina Tripodi ,&nbsp;Valentina Pinna ,&nbsp;Mariateresa Zanobio ,&nbsp;Giovannina Rotundo ,&nbsp;Emanuele Bellacchio ,&nbsp;Francesca Lepri ,&nbsp;Antonella Farina ,&nbsp;Maria Cecilia D’Asdia ,&nbsp;Francesca Piceci-Sparascio ,&nbsp;Tommaso Biagini ,&nbsp;Antonio Petracca ,&nbsp;Marco Castori ,&nbsp;Daniela Melis ,&nbsp;Alessandro De Luca","doi":"10.1016/j.gim.2024.101241","DOIUrl":"10.1016/j.gim.2024.101241","url":null,"abstract":"<div><h3>Purpose</h3><div>Pathogenic <em>LZTR1</em> variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function <em>LZTR1</em> alleles and isolated multiple café-au-lait macules (CaLMs).</div></div><div><h3>Methods</h3><div>A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic <em>NF1</em> and <em>SPRED1</em> variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous <em>LZTR1</em> variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions.</div></div><div><h3>Results</h3><div>Analysis revealed heterozygous <em>LZTR1</em> variants in 6.0% (51/849) of participants, exceeding the general population prevalence. <em>LZTR1</em>-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated but occasionally associated with features recurring in RASopathies. In 2 families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating loss-of-function. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate mitogen-activated protein kinase signaling.</div></div><div><h3>Conclusion</h3><div>Our findings expand the phenotypic variability associated with <em>LZTR1</em> variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101241"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975526","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":"Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations","authors":"Sateesh Maddirevula ,&nbsp;Mohammad Shagrani ,&nbsp;Ae-Ri Ji ,&nbsp;Christopher R. Horne ,&nbsp;Samuel N. Young ,&nbsp;Lucy J. Mather ,&nbsp;Mashael Alqahtani ,&nbsp;Colin McKerlie ,&nbsp;Geoffrey Wood ,&nbsp;Paul K. Potter ,&nbsp;Firdous Abdulwahab ,&nbsp;Tarfa AlSheddi ,&nbsp;Wendy L. van der Woerd ,&nbsp;Koen L.I. van Gassen ,&nbsp;Dalal AlBogami ,&nbsp;Kishwer Kumar ,&nbsp;Ali Syed Muhammad Akhtar ,&nbsp;Hiba Binomar ,&nbsp;Hadeel Almanea ,&nbsp;Eissa Faqeih ,&nbsp;Fowzan S. Alkuraya","doi":"10.1016/j.gim.2024.101231","DOIUrl":"10.1016/j.gim.2024.101231","url":null,"abstract":"<div><h3>Purpose</h3><p>Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly.</p></div><div><h3>Methods</h3><p>In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test.</p></div><div><h3>Results</h3><p>A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (<em>PSKH1</em>) (HGNC:9529) in 4 families. <em>PSKH1</em> was particularly compelling because of strong linkage in 3 consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the 4 families shared a founder homozygous variant, whereas the third and fourth had different homozygous variants in <em>PSKH1</em>. <em>PSKH1</em> encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous <em>Pskh1</em> mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays.</p></div><div><h3>Conclusion</h3><p>Our results support the use of genomics in the workup of pediatric cholestasis and reveal <em>PSKH1</em>-related hepatorenal ciliopathy as a novel candidate monogenic form.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101231"},"PeriodicalIF":6.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916566","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 “Clinical utility of polygenic risk scores for embryo selection: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)” by Grebe et al","authors":"","doi":"10.1016/j.gim.2024.101155","DOIUrl":"10.1016/j.gim.2024.101155","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 8","pages":"Article 101155"},"PeriodicalIF":6.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295915","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":"Response to Widen et al","authors":"","doi":"10.1016/j.gim.2024.101156","DOIUrl":"10.1016/j.gim.2024.101156","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 8","pages":"Article 101156"},"PeriodicalIF":6.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295916","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}