American journal of human genetics最新文献

{"title":"EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.","authors":"Lucia Laugwitz, Rebecca Buchert, Patricio Olguín, Mehrdad A Estiar, Mihaela Atanasova, Wilson Marques Jr, Jörg Enssle, Brian Marsden, Javiera Avilés, Andrés González-Gutiérrez, Noemi Candia, Marietta Fabiano, Susanne Morlot, Susana Peralta, Alisa Groh, Carmen Schillinger, Carolin Kuehn, Linda Sofan, Marc Sturm, Benjamin Bender, Pedro J Tomaselli, Uta Diebold, Amelie J Mueller, Stephanie Spranger, Maren Fuchs, Fernando Freua, Uirá Souto Melo, Lauren Mattas, Setareh Ashtiani, Oksana Suchowersky, Samuel Groeschel, Guy A Rouleau, Keren Yosovich, Marina Michelson, Zvi Leibovitz, Muhammad Bilal, Eyyup Uctepe, Ahmet Yesilyurt, Orhan Ozdogan, Tamer Celik, Ingeborg Krägeloh-Mann, Olaf Riess, Hendrik Rosewich, Muhammad Umair, Dorit Lev, Stephan Zuchner, Ulrich Schweizer, David S Lynch, Ziv Gan-Or, Tobias B Haack","doi":"10.1016/j.ajhg.2024.12.001","DOIUrl":"10.1016/j.ajhg.2024.12.001","url":null,"abstract":"<p><p>Inborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures. Cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. Exome or genome sequencing identified six different bi-allelic EEFSEC variants in nine individuals from eight unrelated families. These variants showed reduced EEFSEC function in vitro, leading to lower levels of selenoproteins in fibroblasts. In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms. This study identifies EEFSEC deficiency as an inborn error of selenocysteine metabolism. It reveals the pathophysiological mechanisms of neurodegeneration linked to selenoprotein metabolism, suggesting potential targeted therapies.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"168-180"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mendelian genetics and eugenics.","authors":"Walter F Bodmer, Brian Charlesworth","doi":"10.1016/j.ajhg.2024.12.003","DOIUrl":"10.1016/j.ajhg.2024.12.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"196-197"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability.","authors":"Pascale Sabeh,Samantha A Dumas,Claudia Maios,Hiba Daghar,Marek Korzeniowski,Justine Rousseau,Matthew Lines,Andrea Guerin,John J Millichap,Megan Landsverk,Theresa Grebe,Kristin Lindstrom,Jonathan Strober,Tarik Ait Mouhoub,Christiane Zweier,Michelle Steinraths,Moritz Hebebrand,Bert Callewaert,Rami Abou Jamra,Monika Kautza-Lucht,Meret Wegler,Paul Kruszka,Candy Kumps,Ehud Banne,Marta Biderman Waberski,Anne Dieux,Sarah Raible,Ian Krantz,Livija Medne,Kieran Pechter,Laurent Villard,Renzo Guerrini,Claudia Bianchini,Carmen Barba,Davide Mei,Xavier Blanc,Christine Kallay,Emmanuelle Ranza,Xiao-Ru Yang,Emily O'Heir,Kirsten A Donald,Serini Murugasen,Zandre Bruwer,Muge Calikoglu,Jennifer M Mathews,Marion Lesieur-Sebellin,Geneviève Baujat,Nicolas Derive,Tyler Mark Pierson,Jill R Murrell,Amelle Shillington,Clothilde Ormieres,Sophie Rondeau,André Reis,Alberto Fernandez-Jaen,Ping Yee Billie Au,David A Sweetser,Lauren C Briere,Nathalie Couque,Laurence Perrin,Jennifer Schymick,Paul Gueguen,Mathilde Lefebvre,Michael Van Andel,Jane Juusola,Stylianos E Antonarakis,J Alex Parker,Barrington G Burnett,Philippe M Campeau","doi":"10.1016/j.ajhg.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2024.11.009","url":null,"abstract":"E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary cartilage transcriptional signatures reflect cell-type-specific molecular pathways underpinning osteoarthritis.","authors":"Georgia Katsoula, John E G Lawrence, Ana Luiza Arruda, Mauro Tutino, Petra Balogh, Lorraine Southam, Diane Swift, Sam Behjati, Sarah A Teichmann, J Mark Wilkinson, Eleftheria Zeggini","doi":"10.1016/j.ajhg.2024.10.019","DOIUrl":"10.1016/j.ajhg.2024.10.019","url":null,"abstract":"<p><p>Translational efforts in osteoarthritis are hampered by a gap in our understanding of disease processes at the molecular level. Here, we present evidence of pronounced transcriptional changes in high- and low-disease-grade cartilage tissue, pointing to embryonic processes involved in disease progression. We identify shared transcriptional programs between osteoarthritis cartilage and cell populations in the human embryonic and fetal limb, pointing to increases in pre-hypertrophic chondrocytes' transcriptional programs in low-grade cartilage and increases in osteoblastic signatures in high-grade disease tissue. We find that osteoarthritis genetic risk signals are enriched in six gene co-expression modules and show that these transcriptional signatures reflect cell-type-specific expression along the endochondral ossification developmental trajectory. Using this network approach in combination with causal inference analysis, we present evidence of a causal effect on osteoarthritis risk for variants associated with the expression of ten genes that have not been previously reported as effector genes in genome-wide association studies in osteoarthritis. Our findings point to key molecular pathways as drivers of cartilage degeneration and identify high-value drug targets and repurposing opportunities.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2735-2755"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A missense variant effect map for the human tumor-suppressor protein CHK2.","authors":"Marinella Gebbia, Daniel Zimmerman, Rosanna Jiang, Maria Nguyen, Jochen Weile, Roujia Li, Michelle Gavac, Nishka Kishore, Song Sun, Rick A Boonen, Rayna Hamilton, Jennifer N Dines, Alexander Wahl, Jason Reuter, Britt Johnson, Douglas M Fowler, Fergus J Couch, Haico van Attikum, Frederick P Roth","doi":"10.1016/j.ajhg.2024.10.013","DOIUrl":"10.1016/j.ajhg.2024.10.013","url":null,"abstract":"<p><p>The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of Saccharomyces cerevisiae cells lacking the CHEK2 ortholog, RAD53, we generated a systematic \"missense variant effect map\" for CHEK2 missense variation. The map reflects known biochemical features of CHK2 while offering new biological insights. It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"111 12","pages":"2675-2692"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D genome topology distinguishes molecular subgroups of medulloblastoma.","authors":"John J Y Lee, Michael J Johnston, Hamza Farooq, Huey-Miin Chen, Subhi Talal Younes, Raul Suarez, Melissa Zwaig, Nikoleta Juretic, William A Weiss, Jiannis Ragoussis, Nada Jabado, Michael D Taylor, Marco Gallo","doi":"10.1016/j.ajhg.2024.10.003","DOIUrl":"10.1016/j.ajhg.2024.10.003","url":null,"abstract":"<p><p>Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD insulation score differences between subtypes were globally not associated with differential gene expression, although we identified few exceptions near genes expressed in the lineages of origin of specific MB subtypes. Our study therefore supports the notion that TAD insulation scores can distinguish MB subtypes independently of their transcriptional differences.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2720-2734"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions.","authors":"Bin Zhu, Avraam Tapinos, Hela Koka, Priscilla Ming Yi Lee, Tongwu Zhang, Wei Zhu, Xiaoyu Wang, Alyssa Klein, DongHyuk Lee, Gary M Tse, Koon-Ho Tsang, Cherry Wu, Min Hua, Chad A Highfill, Petra Lenz, Weiyin Zhou, Difei Wang, Wen Luo, Kristine Jones, Amy Hutchinson, Belynda Hicks, Montserrat Garcia-Closas, Stephen Chanock, Lap Ah Tse, David C Wedge, Xiaohong R Yang","doi":"10.1016/j.ajhg.2024.10.005","DOIUrl":"10.1016/j.ajhg.2024.10.005","url":null,"abstract":"<p><p>Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed paired germline, NATs, and tumor samples from 43 individuals with BC in Hong Kong (HK). We found that single-nucleotide variants (SNVs) were common in NATs, with one-third of NAT samples exhibiting SNVs in driver genes, many of which were present in paired tumor samples. The most frequently mutated genes in both tumor and NAT samples were PIK3CA, TP53, GATA3, and AKT1. In contrast, large-scale aberrations such as somatic CN alterations (SCNAs) and structural variants (SVs) were rarely detected in NAT samples. We generated phylogenetic trees to investigate the evolutionary history of paired NAT and tumor samples. They could be categorized into tumor only, shared, and multiple-tree groups, the last of which is concordant with non-genetic field cancerization. These groups exhibited distinct genomic and epigenomic characteristics in both NAT and tumor samples. Specifically, NAT samples in the shared-tree group showed higher number of mutations, while NAT samples belonging to the multiple-tree group showed a less inflammatory tumor microenvironment (TME), characterized by a higher proportion of regulatory T cells (Tregs) and lower presence of CD14 cell populations. In summary, our findings highlight the diverse evolutionary history in BC NAT/tumor pairs and the impact of field cancerization and TME in shaping the genomic evolutionary history of tumors.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2773-2788"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteome-wide Mendelian randomization and functional studies uncover therapeutic targets for polycystic ovarian syndrome.","authors":"Feida Ni, Feixia Wang, Jing Sun, Mixue Tu, Jianpeng Chen, Xiling Shen, Xiaohang Ye, Ruixue Chen, Yifeng Liu, Xiao Sun, Jianhua Chen, Xue Li, Dan Zhang","doi":"10.1016/j.ajhg.2024.10.008","DOIUrl":"10.1016/j.ajhg.2024.10.008","url":null,"abstract":"<p><p>Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from six genome-wide association studies (GWASs) on plasma proteome. Genetic associations with PCOS were obtained from a large-scale GWAS meta-analysis, FinnGen cohort, and UK Biobank. Colocalization analyses were performed to prioritize the causal role of candidate proteins. Protein-protein interaction (PPI) and druggability evaluation assessed the druggability of candidate proteins. We evaluated the enrichment of tier 1 and 2 candidate proteins in individuals with PCOS and a mouse model and explored the potential application of the identified drug target. Genetically predicted levels of 65 proteins exhibited associations with PCOS risk, with 30 proteins showing elevated levels and 35 proteins showing decreased levels linked to higher susceptibility. PPI analyses revealed that FSHB, POSTN, CCN2, and CXCL11 interacted with targets of current PCOS medications. Eighty medications targeting 20 proteins showed their potential for repurposing as therapeutic targets for PCOS. EGLN1 levels were elevated in granulosa cells and the plasma of individuals with PCOS and in the plasma and ovaries of dehydroepiandrosterone (DHEA)-induced PCOS mouse model. As an EGLN1 inhibitor, administration of roxadustat in the PCOS mouse model elucidated the EGLN1-HIF1α-ferroptosis axis in inducing PCOS and validated its therapeutic effect in PCOS. Our study identifies candidate proteins causally associated with PCOS risk and suggests that targeting EGLN1 provides a promising treatment strategy.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2799-2813"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward trustable use of machine learning models of variant effects in the clinic.","authors":"Mafalda Dias, Rose Orenbuch, Debora S Marks, Jonathan Frazer","doi":"10.1016/j.ajhg.2024.10.011","DOIUrl":"10.1016/j.ajhg.2024.10.011","url":null,"abstract":"<p><p>There has been considerable progress in building models to predict the effect of missense substitutions in protein-coding genes, fueled in large part by progress in applying deep learning methods to sequence data. These models have the potential to enable clinical variant annotation on a large scale and hence increase the impact of patient sequencing in guiding diagnosis and treatment. To realize this potential, it is essential to provide reliable assessments of model performance, scope of applicability, and robustness. As a response to this need, the ClinGen Sequence Variant Interpretation Working Group, Pejaver et al., recently proposed a strategy for validation and calibration of in-silico predictions in the context of guidelines for variant annotation. While this work marks an important step forward, the strategy presented still has important limitations. We propose core principles and recommendations to overcome these limitations that can enable both more reliable and more impactful use of variant effect prediction models in the future.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2589-2593"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly.","authors":"Yulia Mostovoy, Philip M Boone, Yongqing Huang, Kiran V Garimella, Kar-Tong Tan, Bianca E Russell, Monica Salani, Celine E F de Esch, John Lemanski, Benjamin Curall, Jen Hauenstein, Diane Lucente, Tera Bowers, Tim DeSmet, Stacey Gabriel, Cynthia C Morton, Matthew Meyerson, Alex R Hastie, James Gusella, Fabiola Quintero-Rivera, Harrison Brand, Michael E Talkowski","doi":"10.1016/j.ajhg.2024.10.006","DOIUrl":"10.1016/j.ajhg.2024.10.006","url":null,"abstract":"<p><p>Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, and (3) a tool (BigClipper) to discover chromosomal rearrangements from long reads. We applied these technologies across 13 cases with ring chromosomes, Robertsonian translocations, and complex SVs that were unresolved by short reads, followed by validation using optical genome mapping (OGM). Our analyses resolved 10 of 13 cases, including a Robertsonian translocation and all ring chromosomes. Multiple breakpoints were localized to genomic regions previously recalcitrant to sequencing such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We further performed methylation profiling from long-read data to discover phased differential methylation in a gene promoter proximal to a ring fusion, suggesting a long-range position effect (LRPE) with heterochromatin spreading. Breakpoint sequences suggested mechanisms of SV formation such as microhomology-mediated and non-homologous end-joining, as well as non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of Robertsonian translocations and illuminate the structural diversity of ring chromosomes and complex chromosomal rearrangements with implications for genome biology, prediction of LRPEs from integrated multi-omics technologies, and molecular diagnostics in rare disease cases.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2693-2706"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}