NPJ Genomic Medicine最新文献

{"title":"Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13.","authors":"Prince Jacob, Hillevi Lindelöf, Cecilie F Rustad, Vernon Reid Sutton, Shahida Moosa, Prajna Udupa, Anna Hammarsjö, Gandham SriLakshmi Bhavani, Dominyka Batkovskyte, Kristian Tveten, Ashwin Dalal, Eva Horemuzova, Ann Nordgren, Emma Tham, Hitesh Shah, Else Merckoll, Laura Orellana, Gen Nishimura, Katta M Girisha, Giedre Grigelioniene","doi":"10.1038/s41525-023-00380-x","DOIUrl":"10.1038/s41525-023-00380-x","url":null,"abstract":"<p><p>Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"39"},"PeriodicalIF":5.3,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10665555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138295639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Populational pan-ethnic screening panel enabled by deep whole genome sequencing.","authors":"Linfeng Yang, Zhe Lin, Yong Gao, Jianguo Zhang, Huanhuan Peng, Yaqing Li, Jingang Che, Lijian Zhao, Jilin Zhang","doi":"10.1038/s41525-023-00383-8","DOIUrl":"10.1038/s41525-023-00383-8","url":null,"abstract":"<p><p>Birth defect is a global threat to the public health systems. Mitigating neonatal anomalies is hampered by elusive molecular mechanisms of pathogenic mutations and poor subsequent translation into preventative measures. Applying appropriate strategies in China to promote reproductive health is particularly challenging, as the Chinese population compromises complex genomic diversity due to the inclusion of many ethnic groups with distinct genetic backgrounds. To investigate and evaluate the feasibility of implementing a pan-ethnic screening strategy, and guide future reproductive counselling, high-quality variants associated with autosome recessive (AR) diseases derived from the largest publicly available cohort of the Chinese population were re-analysed using a bottom-up approach. The analyses of gene carrier rates (GCRs) across distinct ethnic groups revealed that substantial heterogeneity existed potentially due to diverse evolutionary selection. The sampling population, sequencing coverage and underlying population structure contributed to the differential variants observed between ChinaMAP and the East Asian group in gnomAD. Beyond characteristics of GCR, potential druggable targets were additionally explored according to genomic features and functional roles of investigated genes, demonstrating that phase separation could be a therapeutic target for autosomal recessive diseases. A further examination of estimated GCR across ethnic groups indicated that most genes shared by at least two populations could be utilised to direct the design of a pan-ethnic screening application once sequencing and interpreting costs become negligible. To this end, a list of autosomal recessive disease genes is proposed based on the prioritised rank of GCR to formulate a tiered screening strategy.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"38"},"PeriodicalIF":5.3,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome.","authors":"Bengi Ruken Yavuz, M Kaan Arici, Habibe Cansu Demirel, Chung-Jung Tsai, Hyunbum Jang, Ruth Nussinov, Nurcan Tuncbag","doi":"10.1038/s41525-023-00377-6","DOIUrl":"10.1038/s41525-023-00377-6","url":null,"abstract":"<p><p>Epidemiological studies suggest that individuals with neurodevelopmental disorders (NDDs) are more prone to develop certain types of cancer. Notably, however, the case statistics can be impacted by late discovery of cancer in individuals afflicted with NDDs, such as intellectual disorders, autism, and schizophrenia, which may bias the numbers. As to NDD-associated mutations, in most cases, they are germline while cancer mutations are sporadic, emerging during life. However, somatic mosaicism can spur NDDs, and cancer-related mutations can be germline. NDDs and cancer share proteins, pathways, and mutations. Here we ask (i) exactly which features they share, and (ii) how, despite their commonalities, they differ in clinical outcomes. To tackle these questions, we employed a statistical framework followed by network analysis. Our thorough exploration of the mutations, reconstructed disease-specific networks, pathways, and transcriptome levels and profiles of autism spectrum disorder (ASD) and cancers, point to signaling strength as the key factor: strong signaling promotes cell proliferation in cancer, and weaker (moderate) signaling impacts differentiation in ASD. Thus, we suggest that signaling strength, not activating mutations, can decide clinical outcome.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"37"},"PeriodicalIF":4.7,"publicationDate":"2023-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71484303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Returning incidentally discovered Hepatitis C RNA-seq results to COPDGene study participants.","authors":"Edwin K Silverman, Arthur Y Kim, Barry J Make, Elizabeth A Regan, Jarrett D Morrow, Craig P Hersh, James O'Brien, James D Crapo, Nadia N Hansel, Gerard Criner, Eric L Flenaugh, Douglas Conrad, Richard Casaburi, Russell P Bowler, Nicola A Hanania, R Graham Barr, Surya P Bhatt, Frank C Sciurba, Antonio Anzueto, MeiLan K Han, Charlene E McEvoy, Alejandro P Comellas, Dawn L DeMeo, Richard Rosiello, Jeffrey L Curtis, Tricia Uchida, Carla Wilson, P Pearl O'Rourke","doi":"10.1038/s41525-023-00379-4","DOIUrl":"10.1038/s41525-023-00379-4","url":null,"abstract":"<p><p>The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed and obtained IRB approval for a process of returning HCV research results and an HCV Follow-Up Study questionnaire to capture information about previous HCV diagnosis and treatment information and participant reactions to return of HCV results. During phone calls following the initial HCV notification letter, 84 of 124 participants who could be contacted (67.7%) volunteered that they had been previously diagnosed with HCV infection. Thirty-one of these 124 COPDGene participants were enrolled in the HCV Follow-Up Study. Five of the 31 HCV Follow-Up Study participants did not report a previous diagnosis of HCV. For four of these participants, subsequent clinical HCV testing confirmed HCV infection. Thus, 30/31 Follow-Up Study participants had confirmed HCV diagnoses, supporting the accuracy of the HCV research test results. However, the limited number of participants in the Follow-Up Study precludes an accurate assessment of the false-positive and false-negative rates of the research RNA sequencing evidence for HCV. Most HCV Follow-Up Study participants (29/31) were supportive of returning HCV research results, and most participants found the process for returning HCV results to be informative and not upsetting. Newly diagnosed participants were more likely to be pleased to learn about a potentially curable infection (p = 0.027) and showed a trend toward being more frightened by the potential health risks of HCV (p = 0.11). We conclude that HCV results identified incidentally during transcriptomic research studies can be successfully returned to research study participants with a carefully designed process.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"36"},"PeriodicalIF":5.3,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71413321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNS tumor stroma transcriptomics identify perivascular fibroblasts as predictors of immunotherapy resistance in glioblastoma patients.","authors":"Maksym Zarodniuk, Alexander Steele, Xin Lu, Jun Li, Meenal Datta","doi":"10.1038/s41525-023-00381-w","DOIUrl":"10.1038/s41525-023-00381-w","url":null,"abstract":"<p><p>Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertake a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures in both adult and pediatric CNS disease. We find that CNS lesions - glioblastoma in particular - can be divided into two ECM-based subtypes (ECM^hi and ECM^lo) that are influenced by the presence of perivascular stromal cells resembling cancer-associated fibroblasts (CAFs). Ligand-receptor network analysis predicts that perivascular fibroblasts activate signaling pathways responsible for recruitment of tumor-associated macrophages and promotion of cancer stemness. Our analysis reveals that perivascular fibroblasts are correlated with unfavorable response to immune checkpoint blockade in glioblastoma and poor patient survival across a subset of CNS tumors. We provide insights into new stroma-driven mechanisms underlying immune evasion and immunotherapy resistance in CNS tumors like glioblastoma, and discuss how targeting these perivascular fibroblasts may prove an effective approach to improving treatment response and patient survival in a variety of CNS tumors.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"35"},"PeriodicalIF":5.3,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.","authors":"Anne Slavotinek, Shannon Rego, Nuriye Sahin-Hodoglugil, Mark Kvale, Billie Lianoglou, Tiffany Yip, Hannah Hoban, Simon Outram, Beatrice Anguiano, Flavia Chen, Jeremy Michelson, Roberta M Cilio, Cynthia Curry, Renata C Gallagher, Marisa Gardner, Rachel Kuperman, Bryce Mendelsohn, Elliott Sherr, Joseph Shieh, Jonathan Strober, Allison Tam, Jessica Tenney, William Weiss, Amy Whittle, Garrett Chin, Amanda Faubel, Hannah Prasad, Yusuph Mavura, Jessica Van Ziffle, W Patrick Devine, Ugur Hodoglugil, Pierre-Marie Martin, Teresa N Sparks, Barbara Koenig, Sara Ackerman, Neil Risch, Pui-Yan Kwok, Mary E Norton","doi":"10.1038/s41525-023-00382-9","DOIUrl":"10.1038/s41525-023-00382-9","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"34"},"PeriodicalIF":5.3,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity.","authors":"Na Zhu, Charles A LeDuc, Ilene Fennoy, Blandine Laferrère, Claudia A Doege, Yufeng Shen, Wendy K Chung, Rudolph L Leibel","doi":"10.1038/s41525-023-00376-7","DOIUrl":"10.1038/s41525-023-00376-7","url":null,"abstract":"<p><p>Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with p-value of 3.6e-12 in the UK biobank cohort. Additionally, we identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity and report the clinical histories of these individuals with non-syndromic obesity with no history of neurobehavioral or cognitive disability. The BMI association was replicated in the All of Us whole genome sequencing data. Heterozygous pLoF BSN variants constitute a new etiology for obesity.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"33"},"PeriodicalIF":4.7,"publicationDate":"2023-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10590409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49680341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"uAUG creating variants in the 5'UTR of ENG causing Hereditary Hemorrhagic Telangiectasia.","authors":"Omar Soukarieh, Emmanuelle Tillet, Carole Proust, Charlène Dupont, Béatrice Jaspard-Vinassa, Florent Soubrier, Aurélie Goyenvalle, Mélanie Eyries, David-Alexandre Trégouët","doi":"10.1038/s41525-023-00378-5","DOIUrl":"10.1038/s41525-023-00378-5","url":null,"abstract":"<p><p>Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder. About 80% of cases are caused by pathogenic variants in ACVRL1 (also known as ALK1) and ENG, with the remaining cases being unexplained. We identified two variants, c.-79C>T and c.-68G>A, in the 5'UTR of ENG in two unrelated patients. They create upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon. To assess the pathogenicity of these variants, we performed functional assays based on the expression of wild-type and mutant constructs in human cells and evaluated their effect on ALK1 activity in a BMP-response element assay. This assay is mandatory for molecular diagnosis and has been so far only applied to coding ENG variants. These variants were associated with a decrease of protein levels in HeLa and HUVEC cells and a decreased ability to activate ALK1. We applied the same experiments on three additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) located in the 5'UTR of ENG and previously reported in HHT patients. We found that all the analyzed variants alter protein levels and function. Additional experiments relying on an artificial deletion in our mutated constructs show that identified uAUGs could initiate the translation indicating that the associated effect is translation-dependent. Overall, we have identified two 5'UTR ENG variations in HHT patients and shed new light on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"32"},"PeriodicalIF":5.3,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases.","authors":"Omid Seidizadeh, Andrea Cairo, Luciano Baronciani, Luca Valenti, Flora Peyvandi","doi":"10.1038/s41525-023-00375-8","DOIUrl":"10.1038/s41525-023-00375-8","url":null,"abstract":"<p><p>Von Willebrand disease (VWD) is a common bleeding disorder caused by mutations in the von Willebrand factor gene (VWF). The true global prevalence of VWD has not been accurately established. We estimated the worldwide and within-population prevalence of inherited VWD by analyzing exome and genome data of 141,456 individuals gathered by the genome Aggregation Database (gnomAD). We also extended our data deepening by mining the main databases containing VWF variants i.e., the Leiden Open Variation Database (LOVD) and the Human Gene Mutation Database (HGMD) with the goal to explore the global mutational spectrum of VWD. A total of 4,313 VWF variants were identified in the gnomAD population, of which 505 were predicted to be pathogenic or already reported to be associated with VWD. Among the 282,912 alleles analyzed, 31,785 were affected by the aforementioned variants. The global prevalence of dominant VWD in 1000 individuals was established to be 74 for type 1, 3 for 2A, 3 for 2B and 6 for 2M. The global prevalences for recessive VWD forms (type 2N and type 3) were 0.31 and 0.7 in 1000 individuals, respectively. This comprehensive analysis provided a global mutational landscape of VWF by means of 927 already reported variants in the HGMD and LOVD datasets and 287 novel pathogenic variants identified in the gnomAD. Our results reveal that there is a considerably higher than expected prevalence of putative disease alleles and variants associated with VWD and suggest that a large number of VWD patients are undiagnosed.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"31"},"PeriodicalIF":5.3,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinically significant germline pathogenic variants are missed by tumor genomic sequencing.","authors":"Leigh Anne Stout, Cynthia Hunter, Courtney Schroeder, Nawal Kassem, Bryan P Schneider","doi":"10.1038/s41525-023-00374-9","DOIUrl":"10.1038/s41525-023-00374-9","url":null,"abstract":"<p><p>A germline pathogenic variant may be present even if the results of tumor genomic sequencing do not suggest one. There are key differences in the assay design and reporting of variants between germline and somatic laboratories. When appropriate, both tests should be completed to aid in therapy decisions and determining optimal screening and risk-reduction interventions.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"30"},"PeriodicalIF":5.3,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41207222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}