Genetics in Medicine Open最新文献

{"title":"An evaluation of genetic predisposition to congenital anomalies and pediatric cancer supports KAT6B as a novel neuroblastoma susceptibility gene","authors":"Hyunjung Gu ,&nbsp;Yao Yu ,&nbsp;Saumya Dushyant Sisoudiya ,&nbsp;Pamela Mishra ,&nbsp;He Li ,&nbsp;Jeremy M. Schraw ,&nbsp;Michael E. Scheurer ,&nbsp;Donna M. Muzny ,&nbsp;Danielle Mitchell ,&nbsp;Olga Taylor ,&nbsp;Shalini N. Jhangiani ,&nbsp;Shannon Dugan-Perez ,&nbsp;Yifan Wu ,&nbsp;Harsha Doddapaneni ,&nbsp;Sravya Venkata Bhamidipati ,&nbsp;Marie-Claude Gingras ,&nbsp;Jennifer E. Posey ,&nbsp;Richard A. Gibbs ,&nbsp;Chad D. Huff ,&nbsp;Sharon E. Plon ,&nbsp;Aniko Sabo","doi":"10.1016/j.gimo.2024.101901","DOIUrl":"10.1016/j.gimo.2024.101901","url":null,"abstract":"<div><h3>Purpose</h3><div>Although congenital anomalies are among the strongest risk factors for developing pediatric cancer, the genetic underpinnings remain unclear. Therefore, we evaluated germline susceptibility in children with congenital anomalies and cancer.</div></div><div><h3>Methods</h3><div>Through the Genetic Overlap Between Anomalies and Cancer in Kids Study, we recruited 47 participants with anomalies and cancer, along with their biological families. Genome sequencing was performed, focusing on single-nucleotide variants, indels, and structural variants. Pathogenic or likely pathogenic variants were identified by the American College of Medical Genetics and Genomics classification.</div></div><div><h3>Results</h3><div>We identified pathogenic or likely pathogenic variants in 23.4% (11 of 47) of participants. These variants encompassed (1) 4 genes associated with both anomalies and cancer (<em>WT1</em>, <em>USP9X</em>, <em>PTPN1</em>, and <em>LZTR1</em>), (2) 2 established cancer predisposition genes (<em>TP53</em> in 2 participants and <em>PAX5</em>), and (3) 4 genes that are associated with anomalies (<em>MMUT</em>, <em>FBN1</em>, <em>COL3A1</em>, and <em>KAT6B</em>). We further investigated the role of <em>KAT6B</em> on neuroblastoma in a gene-based analysis from 409 neuroblastoma cases and 952 controls. This analysis demonstrated a significant enrichment of rare, predicted deleterious variants (<em>P</em> = .017), with odds ratios ranging from 2 to 4 based on the conditions we applied.</div></div><div><h3>Conclusion</h3><div>This study demonstrates a molecular diagnostic yield of 23.4% in participants with both anomalies and cancer. Additionally, the findings further implicate the role of <em>KAT6B</em> as a novel neuroblastoma predisposition gene.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101901"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pilot implementation study of a default genetic referral process for patients with early-onset colorectal cancer","authors":"Kelsey S. Lau-Min ,&nbsp;Shavon Rochester ,&nbsp;Megan Grabill ,&nbsp;Jessica M. Long ,&nbsp;Danielle B. McKenna ,&nbsp;Jacqueline Powers ,&nbsp;Danny Bracy ,&nbsp;Leland Boisseau ,&nbsp;Peter Gabriel ,&nbsp;Randall Oyer ,&nbsp;Susan M. Domchek ,&nbsp;Katharine A. Rendle ,&nbsp;Katherine L. Nathanson ,&nbsp;Bryson W. Katona","doi":"10.1016/j.gimo.2024.101902","DOIUrl":"10.1016/j.gimo.2024.101902","url":null,"abstract":"<div><h3>Purpose</h3><div>Early-onset colorectal cancer (CRC) diagnosed under age 50 is increasing at alarming rates, with &gt;75% of early-onset cases occurring in patients between 40 and 49 years old. Germline genetic risk evaluations are key to delivering high-quality care to these patients.</div></div><div><h3>Methods</h3><div>We conducted a single-arm pilot implementation study of a default genetic referral process for patients diagnosed with CRC between ages 40 and 49 at 5 hospitals in an academic health system. A research coordinator notified patients and their oncologists of their eligibility for a default genetic referral, after which all patients who did not opt out were referred for genetic counseling, testing, and result disclosure as per usual care. The primary outcome was the genetic referral rate; secondary outcomes included the percentage of eligible patients who were scheduled for a genetic evaluation, completed genetic counseling, and underwent testing within 3 months of the initial referral. We conducted semistructured exit interviews with a subset of patients and oncologists to elicit feedback on the intervention.</div></div><div><h3>Results</h3><div>We included 53 patients, of whom 49 (92%) were referred to genetics, 38 (72%) were scheduled, 22 (42%) completed genetic counseling, and 13 (25%) underwent testing within 3 months of the initial referral. In exit interviews (<em>n</em> = 10 patients and 10 oncologists), participants reported finding the default genetic referral process acceptable and feasible to implement.</div></div><div><h3>Conclusion</h3><div>A default genetic referral process is acceptable, feasible, and associated with a high referral rate for patients with early-onset CRC; however, subsequent scheduling, evaluation, and testing rates remain suboptimal.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101902"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing","authors":"Youbao Sha ,&nbsp;J. Bryce Ortiz ,&nbsp;Sara L. Bristow ,&nbsp;Kate Loranger ,&nbsp;Linyan Meng ,&nbsp;Xiaonan Zhao ,&nbsp;Fan Xia ,&nbsp;Sheetal Parmar ,&nbsp;Adam C. ElNaggar ,&nbsp;Wenbo Xu","doi":"10.1016/j.gimo.2024.101914","DOIUrl":"10.1016/j.gimo.2024.101914","url":null,"abstract":"<div><h3>Purpose</h3><div>Although up to 25% of germline variants are predicted to affect splicing, most are classified as variants of uncertain significance (VUS) because of the limited understanding of their functional consequences. Here, we investigated the impact of RNA sequencing (RNA-seq) data on the ability to resolve splicing-related VUS.</div></div><div><h3>Methods</h3><div>Patients with VUS predicted to alter splicing identified through commercial hereditary cancer testing between October 2021 to July 2023 were included. RNA-seq was used to compare splicing patterns between patient blood samples and normal controls. VUS reclassification rates were calculated.</div></div><div><h3>Results</h3><div>In total, 411 VUS in 52 genes predicted to affect splicing were included. RNA-seq results resolved 26.3% (108/411) of the VUS: 28 (6.8%) upgraded to pathogenic/likely pathogenic, and 80 (19.5%) downgraded to not reportable. Among the 28 upgraded, 17 (60.7%) were intronic, 9 (32.1%) were exonic missense variants, and 2 (7.1%) were exonic synonymous variants. Most of the VUS downgraded to not reportable were intronic (64/80, 80%). The remaining 16 (20%) of the downgraded VUS were synonymous variants.</div></div><div><h3>Conclusion</h3><div>This study underscores the utility of RNA-seq to detect variants that affect splicing and could have an impact on cancer risk assessment management and treatment.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101914"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An evaluation of practices and policies used in genetics clinics across the United States to manage referrals for Ehlers-Danlos and hypermobility syndromes","authors":"Lauren Boucher ,&nbsp;Berkley Nestler ,&nbsp;Daniel Groepper ,&nbsp;John Quillin ,&nbsp;David Deyle ,&nbsp;Colin M.E. Halverson","doi":"10.1016/j.gimo.2024.101960","DOIUrl":"10.1016/j.gimo.2024.101960","url":null,"abstract":"<div><h3>Purpose</h3><div>Hypermobile Ehlers-Danlos syndrome (hEDS) and joint hypermobility syndrome (JHS), among other conditions, comprise a collection of heritable disorders of connective tissue. There are recognized challenges in diagnosing JHS/hEDS. Despite a lack of identifiable molecular etiology for these conditions, referrals to medical geneticists for evaluation are commonplace, and they continue to rise. Because of an absence of nationally recognized referral guidelines for JHS/hEDS, health care institutions are left to develop their own policies. The purpose of our study was to characterize these ad hoc policies systematically and at a nationwide level.</div></div><div><h3>Methods</h3><div>We conducted a mixed-methods study of 71 board-eligible or board-certified genetic counselors, including 15 qualitative interviews.</div></div><div><h3>Results</h3><div>Cross-case analysis revealed multiple motivations for creating these policies, methods to more effectively manage referrals for hypermobility and concern for EDS, and participants’ evaluations of the successes and shortcomings of these policies at their institutions. We found diverse and unstandardized policies that were meant to address numerous perceived challenges. This lack of standardization is a concern because it may result in inconsistent access to care for patients with JHS/hEDS and create barriers to diagnosis and treatment.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that policies vary widely, and genetic counselors are concerned about the potential impact of this variability on the quality of care for patients with JHS/hEDS.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101960"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143214779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer","authors":"Wen Wen ,&nbsp;Sen Zhao ,&nbsp;Yiwen Jiang ,&nbsp;Chengzhu Ou ,&nbsp;Changyuan Guo ,&nbsp;Ziqi Jia ,&nbsp;Jiayi Li ,&nbsp;Yansong Huang ,&nbsp;Hengyi Xu ,&nbsp;Pengming Pu ,&nbsp;Tongxuan Shang ,&nbsp;Lin Cong ,&nbsp;Xiang Wang ,&nbsp;Nan Wu ,&nbsp;Jiaqi Liu","doi":"10.1016/j.gimo.2024.101899","DOIUrl":"10.1016/j.gimo.2024.101899","url":null,"abstract":"<div><h3>Purpose</h3><div>To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond <em>BRCA1/2</em> (HGNC: 1100, 1101) variants.</div></div><div><h3>Methods</h3><div>Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted <em>BRCA1/2</em> variants followed by GS to identify pathogenic/likely pathogenic germline variants through a 3-tiered classification. Polygenic risk score analysis was further incorporated using a model for female breast cancer with 2666 noncancer controls. Exome sequencing was used to transition from germline to somatic investigations, assessing second-hit variant and mutational signatures.</div></div><div><h3>Results</h3><div>The GS analysis unveiled previously unrecognized pathogenic/likely pathogenic germline variants in <em>BARD1</em>, <em>ATR</em>, <em>BRIP1</em>, and <em>CHEK2</em> (HGNC: 952, 882, 20473, 16627) among 21 <em>BRCA1/2-</em>negative patients with MBC, elevating the diagnostic yield from 12.5% to 33.0% in all MBC. Elevated average polygenic risk score was noted compared with controls, with a significant correlation to early-onset MBC when combined with high-penetrance germline pathogenic variants (<em>P =</em> 1.10 × 10⁻⁴). Exome sequencing analysis further identified significant somatic oncogenic drivers and revealed a dominant mutational signature SBS3 across <em>BRCA1/2-</em>negative samples, reinforcing the contribution of omologous recombination deficiency underlying the MBC development.</div></div><div><h3>Conclusion</h3><div>Our findings extended the MBC genetic spectrum beyond BRCA1/2 and highlighted the intricate interplay of monogenic and polygenic predispositions, presenting a comprehensive MBC genomic profile.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101899"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"College of American Pathologists (CAP)/American College of Medical Genetics and Genomics (ACMG) proficiency testing for urinary glycosaminoglycan analysis: A summary of performance","authors":"Kristina Cusmano-Ozog ,&nbsp;Dietrich Matern ,&nbsp;Thomas Long ,&nbsp;Nicola Longo ,&nbsp;Sarah Young","doi":"10.1016/j.gimo.2024.101912","DOIUrl":"10.1016/j.gimo.2024.101912","url":null,"abstract":"<div><h3>Purpose</h3><div>Glycosaminoglycans (GAGs) accumulate in patients with mucopolysaccharidoses (MPS), multiple sulfatase deficiency, and mucolipidoses; measurement of total GAGs and the specific excretion pattern by fractionation can aid in their diagnosis. Since 1993, the College of American Pathologists with the American College of Medical Genetics and Genomics has offered proficiency testing (PT) for urine GAG analysis accessible to laboratories worldwide.</div></div><div><h3>Methods</h3><div>Data from PT surveys administered from 2016 to 2022 were assessed for trends in participation and methodological platforms used, as well as analytical performance and diagnostic accuracy by method and disease.</div></div><div><h3>Results</h3><div>The number of participating laboratories declined from 43 in 2016 to 28 in 2022. Fourteen urine samples with clinical vignettes were distributed; the median of correct diagnoses reported was 91.5% (range: 74%-100%). The best performing methodologies for total GAG analysis and fractionation were dimethylmethylene blue-dye-binding spectrophotometric assay and liquid chromatography-tandem mass spectrometry, respectively. MPS IV samples posed the greatest diagnostic challenge, whereas the overall false-positive rate was low.</div></div><div><h3>Conclusion</h3><div>Based on the data reviewed, best patient care for those at risk of an MPS is achieved by a combination of total GAG analysis and GAG fractionation. Development of liquid-chromatography-tandem-mass-spectrometry-based methods for quantitative, differentiated GAG analysis or disease-specific GAG-derived nonreducing end oligosaccharide fragments in combination with multiplexed lysosomal enzyme assays will likely improve diagnostic accuracy. The decline of laboratories participating in PT is concerning because MPS are increasingly included in newborn screening programs and urinary GAGs can be used to monitor the effectiveness of new therapies.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101912"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia","authors":"Christina G. Tise ,&nbsp;Katie Ashton ,&nbsp;Lachlan de Hayr ,&nbsp;Kun-Di Lee ,&nbsp;Omkar L. Patkar ,&nbsp;Emma Krzesinski ,&nbsp;Jennifer A. Bassetti ,&nbsp;Erin M. Carter ,&nbsp;Cathleen Raggio ,&nbsp;Andreas Zankl ,&nbsp;Anas M. Khanshour ,&nbsp;Kristhen N. Atala ,&nbsp;Jonathan J. Rios ,&nbsp;Carol A. Wise ,&nbsp;Ying Zhu ,&nbsp;Futao Zhang ,&nbsp;Tony Roscioli ,&nbsp;Michael Buckley ,&nbsp;Robert J. Harvey ,&nbsp;Paul A. Dawson","doi":"10.1016/j.gimo.2024.101958","DOIUrl":"10.1016/j.gimo.2024.101958","url":null,"abstract":"<div><h3>Purpose</h3><div>Sulfate is vital for many physiological processes, including the structural and functional maintenance of macromolecules and formation of sulfur-containing compounds essential for cartilage and bone development. SLC13A1 is a sodium-sulfate cotransporter primarily expressed in the kidney, where it mediates sulfate reabsorption and maintenance of circulating sulfate levels. In this study, we characterized the clinical, biochemical, and functional impact of biallelic <em>SLC13A1</em> nonsense and/or missense variants in individuals presenting with a skeletal phenotype.</div></div><div><h3>Methods</h3><div>Probands were identified by exome or genome sequencing and GeneMatcher. Sulfate levels were quantified using ion chromatography. <em>SLC13A1</em> missense variants p.(Arg237Cys), p.(Gly448Asp), p.(Leu516Pro), and p.(Tyr582His) were characterized using bioinformatics, molecular modeling, and [³⁵S]-sulfate uptake assays in Madin-Darby canine kidney cells.</div></div><div><h3>Results</h3><div>All probands presented with concern for short stature and were found to have scoliosis and/or skeletal dysplasia. A reduction in plasma sulfate level and/or increase in urinary sulfate excretion was detected in 2 of 2 probands evaluated. Functional studies were consistent with <em>SLC13A1</em> variants resulting in the complete loss of sulfate transport activity.</div></div><div><h3>Conclusion</h3><div>Biallelic loss-of-function variants in <em>SLC13A1</em> are a novel cause of skeletal phenotypes in humans with a measurable biomarker. Sulfate measurements should be considered in the clinical interpretation of variants identified in <em>SLC13A1</em>.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101958"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes","authors":"N. Ağaoğlu, Brittany L. Bychkovsky, Carolyn Horton, Min-Tzu Lo, Linda Polfus, Cassidy Carraway, P. Hemyari, Colin Young, Marcy E. Richardson, Rochelle Scheib, Judy E. Garber, H. Rana","doi":"10.1016/j.gimo.2024.101829","DOIUrl":"https://doi.org/10.1016/j.gimo.2024.101829","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139883051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: a survey of LGG Fellowship Program Directors","authors":"Joshua L. Deignan, Vimla Aggarwal, Allen E. Bale, Daniel B. Bellissimo, Jessica K. Booker, Yang Cao, Kristy R. Crooks, Kristen L. Deak, Daniela del Gaudio, Birgit Funke, N. Hoppman, Vanessa L. Horner, Robert B. Hufnagel, Colleen Jackson-Cook, Prasad Koduru, Marco L. Leung, Shibo Li, Pengfei Liu, Minjie Luo, Rong Mao, Heather Mason-Suares, Fady M. Mikhail, Stephen R. Moore, Rizwan Naeem, Laura M. Pollard, Elena A. Repnikova, Lina Shao, Brandon M. Shaw, Shashirekha Shetty, Teresa A. Smolarek, Elizabeth Spiteri, Jessica Van Ziffle, Gail H. Vance, Cindy L. Vnencak-Jones, Eli S. Williams","doi":"10.1016/j.gimo.2024.101820","DOIUrl":"https://doi.org/10.1016/j.gimo.2024.101820","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"99 1-2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139879547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A combination of long- and short-read genomics reveals frequent p-arm breakpoints within chromosome 21 complex genomic rearrangements","authors":"Jakob Schuy ,&nbsp;Kristine Bilgrav Sæther ,&nbsp;Jasmin Lisfeld ,&nbsp;Marlene Ek ,&nbsp;Christopher M. Grochowski ,&nbsp;Ming Yin Lun ,&nbsp;Alex Hastie ,&nbsp;Susanne Rudolph ,&nbsp;Sigrid Fuchs ,&nbsp;Kornelia Neveling ,&nbsp;Maja Hempel ,&nbsp;Alexander Hoischen ,&nbsp;Maria Pettersson ,&nbsp;Claudia M.B. Carvalho ,&nbsp;Jesper Eisfeldt ,&nbsp;Anna Lindstrand","doi":"10.1016/j.gimo.2024.101863","DOIUrl":"10.1016/j.gimo.2024.101863","url":null,"abstract":"<div><h3>Purpose</h3><p>Although chromosome 21 is the smallest human chromosome, it is highly relevant in the pathogenicity of both cancer and congenital diseases, including Alzheimer disease and trisomy 21 (Down syndrome). In addition, cases with rare structural variants (SVs) of chromosome 21 have been reported. These events vary in size and include large chromosomal events, such as ring chromosomes and small partial aneuploidies. The p-arm of the acrocentric chromosome 21 was devoid of reference genomic sequence in GRCh37 and GRCh38, which hampered our ability to solve genomic rearrangements and find the mechanism of formation of disease-causing SVs. We hypothesize that conserved satellite structures and segmental duplications located on the p-arm play an important role in the formation of complex SVs involving chromosome 21.</p></div><div><h3>Methods</h3><p>Three cases with complex chromosome 21 rearrangements were studied with a combination of short-read and long-read genome sequencing, as well as optical genome mapping. The data were aligned to the T2T-CHM13 assembly.</p></div><div><h3>Results</h3><p>We were able to resolve all 3 complex chromosome 21 rearrangements in which 15, 8, and 26 breakpoints were identified, respectively. By comparing the identified SV breakpoints, we were able to pinpoint a region between 21p13 and 21p12 that appears to be frequently involved in chromosome 21 rearrangements. Importantly, we observed acrocentric satellite DNA at several breakpoint junctions suggesting an important role for those elements in the formation of complex SVs.</p></div><div><h3>Conclusion</h3><p>Taken together, our results provide further insights into the architecture and underlying mechanisms of complex rearrangements on acrocentric chromosomes.</p></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"2 ","pages":"Article 101863"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949774424010094/pdfft?md5=1809b99be367e12f5c3447c0dac9c534&pid=1-s2.0-S2949774424010094-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}