Genetics in Medicine最新文献

{"title":"The CAP/ACMG CYCGH proficiency testing program: 10 years in review","authors":"Yassmine Akkari ,&nbsp;Laura Conlin ,&nbsp;Diana DeAvila ,&nbsp;Juli-Anne Gardner ,&nbsp;Jaimie Halley ,&nbsp;Gordana Raca ,&nbsp;Reha M. Toydemir ,&nbsp;Karen Tsuchiya ,&nbsp;Catherine Rehder ,&nbsp;CAP/ACMG Cytogenetics Committee","doi":"10.1016/j.gim.2025.101445","DOIUrl":"10.1016/j.gim.2025.101445","url":null,"abstract":"<div><h3>Purpose</h3><div>The College of American Pathologists has offered proficiency testing (PT) for the detection of copy-number variations (CNV) in the constitutional setting (CYCGH) since 2008. We review and summarize data from the CYCGH PT program, including participant performance over time, changes made to the program, and ungraded challenges.</div></div><div><h3>Methods</h3><div>The PT challenges from 2011 through 2021 (22 total mailings) and changes to the program over time were reviewed. Laboratory enrollment and performance were assessed.</div></div><div><h3>Results</h3><div>Overall participation has increased over time, and laboratories have maintained a high level of proficiency. The major changes to the program have occurred twice during the time span examined. Reasons for challenges not meeting consensus were varied. The use of ungraded challenges was also discussed.</div></div><div><h3>Conclusion</h3><div>The CYCGH PT program is challenging because it assesses both analytical performance and interpretation as a single analyte. The program has evolved over time to address the changes in the field of CNV detection. During this time, additional technologies with the ability to detect CNVs have emerged, and the possibility of developing a platform-agnostic CNV PT program is being explored.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101445"},"PeriodicalIF":6.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991631","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":"Nonadherence to guidelines for genetic testing in families with ovarian cancer shows racial bias","authors":"Jacklyn O. Omorodion ,&nbsp;Aparna Nathan ,&nbsp;Stuart Lipsitz ,&nbsp;Satoshi Koyama ,&nbsp;Emma Perez ,&nbsp;Robert C. Green ,&nbsp;Pradeep Natarajan ,&nbsp;Nina B. Gold","doi":"10.1016/j.gim.2025.101444","DOIUrl":"10.1016/j.gim.2025.101444","url":null,"abstract":"<div><h3>Purpose</h3><div>The National Comprehensive Cancer Network (NCCN) recommends germline genetic testing for individuals at risk for hereditary ovarian cancer. We sought to determine the proportion and characteristics of individuals meeting testing criteria in a multicenter biobank who were appropriately offered testing.</div></div><div><h3>Methods</h3><div>In this retrospective cohort study, we identified Mass General Brigham Biobank participants meeting genetic testing criteria per NCCN guidelines. Logistic regression was used to analyze sociodemographic factors associated with which participants were offered testing, completed testing, and had a family history that matched their self-report documented in the electronic medical record.</div></div><div><h3>Results</h3><div>Most eligible participants (909/1441, 63.1%) were not offered genetic testing. Participants who were Black or Hispanic had a lower likelihood of being offered testing. Compared with self-report, 988 (68.6%) participants had a family history of ovarian cancer documented in their electronic medical record. Older age, Hispanic ethnicity, and public insurance use were associated with decreased likelihoods of accurate family history documentation. Correct documentation was associated with an increased likelihood of being offered testing.</div></div><div><h3>Conclusion</h3><div>The majority of participants in this study did not receive NCCN-compliant care. Germline genetic testing for hereditary ovarian cancer screening is underutilized and access to this testing is currently inequitable.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101444"},"PeriodicalIF":6.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976722","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":"C-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder","authors":"Jung-Wan Mok ,&nbsp;Laura Mackay ,&nbsp;Maria Blazo ,&nbsp;Elizabeth Mizerik ,&nbsp;Jozef Gecz ,&nbsp;Renee Carroll ,&nbsp;Mathilde Nizon ,&nbsp;Sophie Rondeau ,&nbsp;Madeleine Joubert ,&nbsp;Silvestre Cuinat ,&nbsp;Wallid Deb ,&nbsp;Fernanda Valle Sirias ,&nbsp;Monika Weisz-Hubshman ,&nbsp;Shamika Ketkar ,&nbsp;Urszula Polak ,&nbsp;Alyssa A. Tran ,&nbsp;Debra Kearney ,&nbsp;Neil A. Hanchard ,&nbsp;Oguz Kanca ,&nbsp;Michael F. Wangler ,&nbsp;Keren Machol","doi":"10.1016/j.gim.2025.101429","DOIUrl":"10.1016/j.gim.2025.101429","url":null,"abstract":"<div><h3>Purpose</h3><div><em>GPKOW</em>, a gene on the X-chromosome, encodes a nuclear RNA-binding protein important in messenger RNA (mRNA) processing as a spliceosome subunit. This work aims to establish <em>GPKOW</em> as a disease-associated gene.</div></div><div><h3>Methods</h3><div>We describe 3 males from 2 unrelated families with hemizygous frameshift variants affecting the last exon of <em>GPKOW</em> p.(Arg441SerfsTer30) and p.(Ser444GlufsTer28). The effect of p.(Ser444GlufsTer28) on gene expression was evaluated in patient’s fibroblasts. In vivo studies in <em>Drosophila melanogaster</em> targeting the sole <em>GPKOW</em> fly ortholog<em>, CG10324</em> (<em>Gpkow)</em> were performed.</div></div><div><h3>Results</h3><div>Clinical presentations included intrauterine growth restriction, microcephaly/microencephaly, and eye, brain, skin, and skeletal abnormalities. Heterozygote females presented with short stature, microcephaly, and vision problems. Sequencing of fibroblasts’ mRNA confirmed that <em>GPKOW</em> mRNA escapes nonsense-mediated decay. Yet, reduced protein levels suggested protein instability. Studies in <em>Drosophila</em> showed that <em>Gpkow</em> is essential and broadly expressed. It is enriched in neurons and glia in eyes and head of developing and adult flies. Knockdown and overexpression of <em>Gpkow</em> in the fly eye cause eyeless/headless phenotype, suggesting that the gene is dosage sensitive. Importantly, overexpression of the p.(Ser444GlufsTer28) variant caused milder defects than the reference allele, indicating that the truncated protein behaves as a partial loss-of-function allele.</div></div><div><h3>Conclusion</h3><div>Rare variants in <em>GPKOW</em> cause a multisystemic X-linked syndrome.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101429"},"PeriodicalIF":6.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016440","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":"Trio exome sequencing in individuals with CAKUT identifies de novo variants in potential novel candidate genes in 19.62.","authors":"Lea Maria Merz, Caroline M Kolvenbach, Chunyan Wang, Nils David Mertens, Steve Seltzsam, Bshara Mansour, Bixia Zheng, Sophia Schneider, Luca Schierbaum, Selina Hölzel, Daanya Salmanullah, Dalia Pantel, Gina Kalkar, Dervla M Connaughton, Nina Mann, Chen-Han Wilfred Wu, Franziska Kause, Makiko Nakayama, Rufeng Dai, Ronen Schneider, Florian Buerger, Camille Nicolas-Frank, Kirollos Yousef, Katharina Lemberg, Ken Saida, Seyoung Yu, Izzeldin Elmubarak, Gijs A C Franken, Kraisoon Lomjansook, Alina Braun, Stuart B Bauer, Nancy M Rodig, Michael J G Somers, Avram Z Traum, Deborah R Stein, Ankana Daga, Michelle A Baum, Ghaleb H Daouk, Hazem S Awad, Loai A Eid, Sherif El Desoky, Mohammed A Shalaby, Jameela A Kari, Said Ooda, Hanan M Fathy, Neveen A Soliman, Marwa Nabhan, Safaa Abdelrahman, Alina C Hilger, Shrikant M Mane, Michael A Ferguson, Velibor Tasic, Shirlee Shril, Friedhelm Hildebrandt","doi":"10.1016/j.gim.2025.101432","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101432","url":null,"abstract":"<p><strong>Purpose: </strong>Congenital anomalies of the kidney and urinary tract (CAKUT) encompass heterogenous malformations arising from defective nephrogenesis. To date, approximately 50 monogenic genes are known to cause CAKUT if mutated. Recent studies show the impact of de novo variants in genetic disease etiology. Hence, this study aimed to identify potential novel CAKUT disease genes with de novo variants.</p><p><strong>Methods: </strong>We performed trio-based exome sequencing (ES) in 209 families with CAKUT to detect novel candidate disease genes.</p><p><strong>Results: </strong>Trio analysis yielded in the identification of CAKUT candidate genes in 96 of 209 trio families (45.93%). In 41 of 209 cases, we detected strong de novo variants in 45 potential novel CAKUT candidate genes (19.62%). We developed a prioritization approach that highlights a truncating de novo variant in SOX13 (HGNC:11192) as a promising cause for CAKUT. In addition, further allele carriers for the candidate gene CHD1L (HGNC:1916) were identified, thus supporting the role of CHD1L in the pathogenesis of CAKUT.</p><p><strong>Conclusion: </strong>We conclude that de novo variants in potential novel CAKUT candidate genes contribute to the disease etiology and present SOX13 as a potential novel cause for CAKUT.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101432"},"PeriodicalIF":6.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984855","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":"Substitutions of nucleotides at the 3′ ends of COL6A1/2/3 exons induce exon skipping associated with collagen VI-related muscular dystrophies and therapeutic strategies","authors":"Seung-Ah Lee ,&nbsp;Megumu Ogawa ,&nbsp;Yoshihiko Saito ,&nbsp;Rui Shimazaki ,&nbsp;Tomonari Awaya ,&nbsp;Motoyasu Hosokawa ,&nbsp;Ryo Kurosawa ,&nbsp;Hiroaki Ohara ,&nbsp;Akihide Takeuchi ,&nbsp;Shinichiro Hayashi ,&nbsp;Yu-ichi Goto ,&nbsp;Masatoshi Hagiwara ,&nbsp;Ichizo Nishino ,&nbsp;Satoru Noguchi","doi":"10.1016/j.gim.2025.101431","DOIUrl":"10.1016/j.gim.2025.101431","url":null,"abstract":"<div><h3>Purpose</h3><div>Collagen VI-related muscular dystrophies, characterized by proximal muscle weakness and joint contractures, are caused by pathogenic variants in the genes, <em>COL6A1</em> to <em>COL6A3</em>. A monoallelic variant at the last nucleotide of a <em>COL6A1</em> exon was initially classified as a missense variant but acted as a splicing variant, resulting in exon skipping. Here, we evaluated whether single-nucleotide variants at the 3′-ends of <em>COL6A1</em> to <em>COL6A3</em> exons cause aberrant splicing.</div></div><div><h3>Methods</h3><div>Ten relevant variants were identified in patients from our repository or public databases, and their muscle <em>COL6A1</em> to <em>COL6A3</em> transcripts were analyzed. The effects of the variants on splicing were also analyzed by minigene assay and SpliceAI in silico prediction.</div></div><div><h3>Results</h3><div>Transcripts from muscles of individuals with suspected collagen VI-related phenotypes showed exon skipping (skipping rate &gt;12%). Findings of minigene assay and in silico prediction experiments supported these findings. Two therapeutic approaches, splicing correction of pre-messenger RNA or gene silencing of mature messenger RNA were assessed. Among them, gene silencing using short interfering RNAs targeting the skipped transcripts proved to be effective in restoring collagen VI in cells containing the pathogenic variant.</div></div><div><h3>Conclusion</h3><div>Single-nucleotide variants at the 3′-ends of exons can lead to aberrant splicing, and allele-specific gene silencing targeting such variants is a promising therapeutic strategy.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101431"},"PeriodicalIF":6.6,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947623","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":"Reporting ABCD1 variants as actionable secondary findings on exome and genome sequencing","authors":"Carlos A. Dominguez Gonzalez ,&nbsp;Nancy B. Spinner ,&nbsp;Rebecca C. Ahrens-Nicklas ,&nbsp;Lisa R. Young ,&nbsp;Laura A. Voss ,&nbsp;Sara L. Reichert ,&nbsp;Daniel J. Gallo ,&nbsp;Julie S. Cohen ,&nbsp;Joshua L. Bonkowsky ,&nbsp;Stephanie R. Keller ,&nbsp;Mariko L. Bennett ,&nbsp;Amy M. Pizzino ,&nbsp;Meghan Swantkowski ,&nbsp;Kaley Arnold ,&nbsp;Jamie L. Fraser ,&nbsp;Felicity J. Emerson ,&nbsp;Kelly Miettunen ,&nbsp;Ali Fatemi ,&nbsp;Keith P. Van Haren ,&nbsp;Laura Adang ,&nbsp;Adeline Vanderver","doi":"10.1016/j.gim.2025.101425","DOIUrl":"10.1016/j.gim.2025.101425","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101425"},"PeriodicalIF":6.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811066","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":"Estimation of the number of people with Down syndrome living in Canada","authors":"Gert de Graaf ,&nbsp;Laura LaChance ,&nbsp;Frank Buckley ,&nbsp;Brian G. Skotko","doi":"10.1016/j.gim.2025.101422","DOIUrl":"10.1016/j.gim.2025.101422","url":null,"abstract":"<div><h3>Purpose</h3><div>We estimate the live births (LBs), selective terminations, miscarriages, and overall population with Down syndrome (DS) in Canada from 1950 to 2020. This study adds to previous work from the United States, Europe, Australia, and New Zealand.</div></div><div><h3>Methods</h3><div>The LBs with DS—in the absence of DS-related terminations—were estimated on the maternal age distribution in the general population. Actual LBs were modeled on registry data. We applied constructed survival curves to annual LBs to estimate population numbers.</div></div><div><h3>Results</h3><div>In 2020, there were an estimated 418 LBs with DS in Canada. As a result of DS-related elective terminations, there were 54% fewer children with DS born than potentially could have been born in Canada, as of 2020. The estimated number of people with DS in Canada has increased from 5138 people in 1950 to 22,367 in 2020.</div></div><div><h3>Conclusion</h3><div>Although, in recent years, the population size of people with DS is decreasing in Australia, New Zealand, and Europe, the number of people with DS is still growing in the United States and Canada. In Canada, however, the growth rate is increasingly slowing down, probably foreshadowing a population contraction in the coming years.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101422"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The development and evaluation of polygenic risk score reports: A systematized review of the literature","authors":"Mia Hanley ,&nbsp;Sharne Limb ,&nbsp;Rebecca Purvis ,&nbsp;Sibel Saya ,&nbsp;Paul Andrew James ,&nbsp;Laura Elenor Forrest","doi":"10.1016/j.gim.2025.101426","DOIUrl":"10.1016/j.gim.2025.101426","url":null,"abstract":"<div><h3>Purpose</h3><div>The return of polygenic risk scores (PGS) is currently being assessed in research settings for clinical utility and validity, and it is anticipated that PGS will soon be implemented in a clinical setting. There are limited guidelines regarding PGS communication and reporting; thus, there is a need to identify and analyze the current research to determine the most acceptable means of presenting PGS results through reports. The aim of this review is to examine the literature regarding the development and evaluation of PGS communication tools, including risk reports, visual aids, and online tools.</div></div><div><h3>Methods</h3><div>Research studies that evaluated preferences, understanding or interpretation of PGS through a report, visual aid, or tool were included. The search strategy was applied to MEDLINE (via Ovid) and American Psychological Association PsychInfo.</div></div><div><h3>Results</h3><div>Thirteen studies met the inclusion criteria. The presentation of PGS differed across studies, including icon arrays and bell curves for visual presentation and absolute risk, relative risk, and genetic risk score for numerical presentation. Participants’ understanding of PGS differed between studies. Studies supported using absolute risk and avoiding stigmatizing colors to communicate results.</div></div><div><h3>Conclusion</h3><div>To support PGS clinical implementation, the development of an evidence-based PGS report evaluated by consumers and various health care professionals is needed.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101426"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803099","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":"Outcomes and effectiveness of decision aids for families affected by hereditary cancer syndromes: A scoping review","authors":"Sun Young Park ,&nbsp;Youlim Kim ,&nbsp;Maria C. Katapodi ,&nbsp;Yeon-Joo Kim ,&nbsp;Heejung Chae ,&nbsp;Yoon-Jung Choi ,&nbsp;Kum Hei Ryu ,&nbsp;Eun-Gyeong Lee ,&nbsp;Sun-Young Kong ,&nbsp;So-Youn Jung","doi":"10.1016/j.gim.2025.101424","DOIUrl":"10.1016/j.gim.2025.101424","url":null,"abstract":"<div><h3>Purpose</h3><div>In the past 15 years, numerous decision aids (DAs) have been developed to assist families affected by hereditary cancer syndromes in decision-making for managing inheritance and cancer risk. We identified the range and characteristics of DAs, focusing on their development stage according to guideline recommendations, their outcomes, and effectiveness.</div></div><div><h3>Methods</h3><div>A comprehensive search was conducted in MEDLINE, EMBASE, Cochrane, CINAHL, and PsycINFO, along with manual searches. Eligible articles reported DAs for supporting families affected by hereditary cancer syndromes, published in English from inception to July 2024. Quality was assessed using the Mixed-Methods Appraisal Tool.</div></div><div><h3>Results</h3><div>From 15,066 records, 32 studies with a moderate risk of bias, reporting 23 unique DAs, were identified. Most DAs targeted women (69.6%) with hereditary breast and ovarian cancer syndrome (73.9%) in North America and Europe (81.3%), primarily supporting decisions on cancer risk-reduction strategies (56.5%) and genetic testing/counseling (47.8%). Only 4 DAs were consistent with guideline-recommended development process, including prototype development, alpha- and beta-testing. Development and alpha-testing outcomes included user experience, understandability, and psychological impact. Beta-testing evaluated decision-making capacity, quality of the decision-making process, psychological impact, and impact on decisions. DAs consistently improved decision-making capacity and quality of the decision-making process but showed variable effects on psychological outcomes and actual decision in risk management.</div></div><div><h3>Conclusion</h3><div>DAs are underdeveloped for genetic, racial, or gender minorities, according to guideline-recommended development process. Future research should develop DAs for broader populations and clarify their effectiveness, particularly regarding psychological outcomes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101424"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803097","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 literature review and pooled case analysis of cardiofaciocutaneous syndrome to estimate cancer risk","authors":"Jazmyn Bess ,&nbsp;Toniya Brown ,&nbsp;Sonia Bhala ,&nbsp;Anaqa Faizer ,&nbsp;Muzzammil Ahmadzada ,&nbsp;Alicia A. Livinski ,&nbsp;Alex Pemov ,&nbsp;Jung Kim ,&nbsp;Philip S. Rosenberg ,&nbsp;Gina M. Ney ,&nbsp;Douglas R. Stewart","doi":"10.1016/j.gim.2025.101423","DOIUrl":"10.1016/j.gim.2025.101423","url":null,"abstract":"<div><h3>Purpose</h3><div>We quantified cancer risk in cardiofaciocutaneous syndrome (CFC), a rare RASopathy.</div></div><div><h3>Methods</h3><div>From a comprehensive search, we reviewed articles from 5 databases and abstracted CFC cases with a clinical and/or molecular diagnosis to form a retrospective cohort. We collected information on <em>BRAF</em>, <em>KRAS</em>, <em>MAP2K1</em>, and <em>MAP2K2</em> genetic variants when available. Genotype-phenotype (cancer) correlations, standardized incidence ratios (SIRs) with age stratification, cumulative incidence and cause-specific hazard rates for cancer and cancer-free in CFC were calculated. A sensitivity analysis with molecular diagnoses only was also performed.</div></div><div><h3>Results</h3><div>This study included 198 publications reporting 690 individuals. Only 1.6% (11) had cancer, including acute lymphoblastic leukemia. Six individuals had cancer and harbored pathogenic variants within <em>BRAF, MAP2K1</em>, and <em>MAP2K2</em>. Cumulative incidence by age 10 was 5% for cancer or cancer-free death. Hazard Ratio (death) was 1% to 2% until age 3 and declined thereafter. Significant SIRs were found for all sites (SIR = 4.96) and acute lymphoblastic leukemia (SIR = 24.23).</div></div><div><h3>Conclusion</h3><div>To our knowledge, this is the largest investigation of cancer in CFC to date. Cancer risk in the CFC population was elevated but appears to be limited to younger than age 3. However, modest case and cancer numbers limit accurate assessments of cancer risk in CFC and more studies are needed.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101423"},"PeriodicalIF":6.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803091","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}