HGG Advances最新文献

{"title":"CUL3-Related Neurodevelopmental Disorder: Clinical Phenotype of 20 New Individuals and Identification of a Potential Phenotype-Associated Episignature.","authors":"Liselot van der Laan, Ananília Silva, Lotte Kleinendorst, Kathleen Rooney, Sadegheh Haghshenas, Peter Lauffer, Yasemin Alanay, Pratibha Bhai, Alfredo Brusco, Sonja de Munnik, Bert B A de Vries, Angelica Delgado Vega, Marc Engelen, Johanna C Herkert, Ron Hochstenbach, Saskia Hopman, Sarina G Kant, Ryutaro Kira, Mitsuhiro Kato, Boris Keren, Hester Y Kroes, Michael A Levy, Ngu Lock-Hock, Saskia M Maas, Grazia M S Mancini, Carlo Marcelis, Naomichi Matsumoto, Takeshi Mizuguchi, Alessandro Mussa, Cyril Mignot, Anu Närhi, Ann Nordgren, Rolph Pfundt, Abeltje M Polstra, Slavica Trajkova, Yolande van Bever, Marie José van den Boogaard, Jasper J van der Smagt, Tahsin Stefan Barakat, Mariëlle Alders, Marcel M A M Mannens, Bekim Sadikovic, Mieke M van Haelst, Peter Henneman","doi":"10.1016/j.xhgg.2024.100380","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100380","url":null,"abstract":"<p><p>Neurodevelopmental disorder with or without autism or seizures (NEDAUS; OMIM #619239) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase; OMIM #603136) haploinsufficiency. We collected clinical and molecular data from twenty-six individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including twenty previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge into the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we preformed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying twenty new individuals and confirming five previously reported cases of NEDAUS.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584446","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":"Chronic Overlapping Pain Conditions and Nociplastic Pain.","authors":"Keira J A Johnston, Rebecca Signer, Laura M Huckins","doi":"10.1016/j.xhgg.2024.100381","DOIUrl":"10.1016/j.xhgg.2024.100381","url":null,"abstract":"<p><p>Chronic Overlapping Pain Conditions (COPCs) are a subset of chronic pain conditions commonly comorbid with one another and more prevalent in women and assigned female at birth (AFAB) individuals. Pain experience in these conditions may better fit with a new mechanistic pain descriptor, nociplastic pain, and nociplastic pain may represent a shared underlying factor among COPCs. We applied GenomicSEM common-factor genome wide association study (GWAS) and multivariate transcriptome-wide association (TWAS) analyses to existing GWAS output for six COPCs in order to find genetic variation associated with nociplastic pain, followed by genetic correlation (linkage-disequilibrium score regression), gene-set and tissue enrichment analyses. We found 24 independent single nucleotide polymorphisms (SNPs), and 127 unique genes significantly associated with nociplastic pain, and showed nociplastic pain to be a polygenic trait with significant SNP-heritability. We found significant genetic overlap between multisite chronic pain and nociplastic pain, and to a smaller extent with rheumatoid arthritis and a neuropathic pain phenotype. Tissue enrichment analyses highlighted cardiac and thyroid tissue, and gene set enrichment analyses emphasized potential shared mechanisms in cognitive, personality, and metabolic traits and nociplastic pain along with distinct pathology in migraine and headache. We use a well-powered network approach to investigate nociplastic pain using existing COPC GWAS output, and show nociplastic pain to be a complex, heritable trait, in addition to contributing to understanding of potential mechanisms in development of nociplastic pain.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577061","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":"Expanding the phenotypic spectrum of CSNK2A1-associated Okur-Chung neurodevelopmental syndrome.","authors":"Swetha Ramadesikan, Iftekhar A Showpnil, Mohammad Marhabaie, Allison Daley, Elizabeth A Varga, Umamaheswaran Gurusamy, Matthew T Pastore, Emily R Sites, Murugu Manickam, Dennis W Bartholomew, Jesse M Hunter, Peter White, Richard K Wilson, Rolf W Stottmann, Daniel C Koboldt","doi":"10.1016/j.xhgg.2024.100379","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100379","url":null,"abstract":"<p><p>De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported , but the third variant (c.137G>T p.Gly46Val) is novel, and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with 1/3^rd presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS which may not be apparent at birth.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577062","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":"Letter to the Editor: Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.","authors":"Eleanor Karp-Tatham, Callum R O'Neill, Julian C Knight, Alexander J Mentzer, Amanda Y Chong","doi":"10.1016/j.xhgg.2024.100382","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100382","url":null,"abstract":"<p><p>Research into HLA-B*15:01 association with asymptomatic SARS-CoV-2 infection has so far yielded contradicting results. Using the UK Biobank cohort, we found a significant association between HLA-B*15:01 and asymptomatic infection. Our study adds more evidence for the complex role HLA alleles play in SARS-Cov-2 infection severity.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568658","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":"RLIM-specific activity reporters define variant pathogenicity in Tonne-Kalscheuer syndrome.","authors":"Venkateshwarlu Bandi, Martin Rennie, Intisar Koch, Polly Gill, Oscar D Pacheco, Aaron D Berg, Hong Cui, D Isum Ward, Francisco Bustos","doi":"10.1016/j.xhgg.2024.100378","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100378","url":null,"abstract":"<p><p>Tonne-Kalscheuer syndrome (TOKAS, OMIM # 300978) is an X-linked recessive disorder with devastating consequences for patients such as intellectual disability, developmental delay, and multiple congenital abnormalities. TOKAS is associated with hemizygous variants in the RLIM gene that encodes a RING-type E3 ubiquitin ligase. The current sustained increase in reported RLIM variants of uncertain significance creates an urgent need to develop assays that can screen these variants and experimentally determine their pathogenicity and disease association. Here, we engineered flow cytometry-based RLIM-specific reporters to measure RLIM activity in TOKAS. This paper describes the design and use of RLIM-specific reporters to determine the pathogenicity of a TOKAS RLIM gene variant. Our data demonstrates that RLIM-specific flow cytometry reporters based on either the full length or a degron region of the substrate REX1 measure RLIM activity in cells. Further, we describe the TOKAS variant RLIM p.Asn581Lys and using reporter assays, determine that it disrupts RLIM catalytic activity. This data reveals how the p.Asn581Lys variant impairs RLIM function and suggests pathogenic mechanisms. The use of RLIM-specific reporters will greatly accelerate the resolution of variants of uncertain significance and disease association in TOKAS.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558997","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":"Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification.","authors":"Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu","doi":"10.1016/j.xhgg.2024.100377","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100377","url":null,"abstract":"<p><p>Epileptic encephalopathies are severe epilepsy syndromes characterized by early onset and progressive cerebral dysfunction. A nonsense variant in the DALR Anticodon Binding Domain Containing 3 (DALRD3) gene has been implicated in epileptic encephalopathy but no other disease-associated variants in DALRD3 have been described. In human cells, the DALRD3 protein forms a complex with the METTL2 methyltransferase to generate the 3-methylcytosine (m3C) modification in specific arginine tRNAs. Here, we identify an individual with a homozygous missense variant in DALRD3 who displays developmental delay, cognitive deficiencies, and multifocal epilepsy. The missense variant substitutes an arginine residue to cysteine (R517C) within the DALR domain of the DALRD3 protein that is required for binding tRNAs. Cells derived from the individual homozygous for the DALRD3-R517C variant exhibit reduced levels of m3C modification in arginine tRNAs, indicating that the R517C variant impairs DALRD3 function. Notably, the DALRD3-R517C protein displays reduced association with METTL2 and loss of interaction with substrate tRNAs. Our results uncover another loss-of-function variant in DALRD3 linked to epileptic encephalopathy disorders. Importantly, these findings underscore DALRD3-dependent tRNA modification as a key contributor to proper brain development and function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558996","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":"Advancements in genetic research by the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): A 10-year Retrospective Review.","authors":"Hridya Rao, Margaret C Weiss, Jee Young Moon, Krista M Perreira, Martha L Daviglus, Robert Kaplan, Kari E North, Maria Argos, Lindsay Fernández-Rhodes, Tamar Sofer","doi":"10.1016/j.xhgg.2024.100376","DOIUrl":"10.1016/j.xhgg.2024.100376","url":null,"abstract":"<p><p>The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, longitudinal cohort study designed to evaluate environmental, lifestyle, and genetic risk factors as they relate to cardiometabolic and other chronic diseases among Hispanic/Latino populations in the United States. Since the study's inception in 2008, as a result of the study's robust genetic measures, HCHS/SOL has facilitated major contributions to the field of genetic research. This 15-year retrospective review highlights the major findings for genotype phenotype relationships and advancements in statistical methods owing to the HCHS/SOL. Furthermore, we discuss the ethical and societal challenges of genetic research, especially among Hispanic/Latino adults in the U.S. Continued genetic research, ancillary study expansion, and consortia collaboration through HCHS/SOL will further drive knowledge and advancements in human genetics research.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547996","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":"Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis.","authors":"Marcos Chiñas, Daniela Fernandez-Salinas, Vitor R C Aguiar, Victor E Nieto-Caballero, Micah Lefton, Peter A Nigrovic, Joerg Ermann, Maria Gutierrez-Arcelus","doi":"10.1016/j.xhgg.2024.100375","DOIUrl":"10.1016/j.xhgg.2024.100375","url":null,"abstract":"<p><p>Multiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased functional genomics approach. We integrated genome-wide association study (GWAS) data with epigenomic and transcriptomic datasets of human immune cells. To quantify enrichment of cell type-specific open chromatin or gene expression in AS risk loci, we used three published methods - LDSC-SEG, SNPsea, scDRS - that have successfully identified relevant cell types in other diseases. Natural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA-seq data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Using the human Space-Time Gut Cell Atlas, we also found significant upregulation of AS-associated genes predominantly in NK cells. We performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes. This revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci, ERAP1 and TNFRSF1A, and two under-studied loci, ENTR1 (aka SDCCAG3) and B3GNT2. Our findings suggest that NK cells may play a crucial role in AS development and highlight four putative target genes for functional follow-up in NK cells.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523261","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":"Variants in the β-globin Locus are Associated with Pneumonia in African American Children.","authors":"Nadine L N Halligan, Sarah C Hanks, Karen Matsuo, Taylor Martins, Sebastian Zöllner, Michael W Quasney, Laura J Scott, Mary K Dahmer","doi":"10.1016/j.xhgg.2024.100374","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100374","url":null,"abstract":"<p><p>In African American adults, the strongest genetic predictor of pneumonia appears to be the A allele of rs334, a variant in the β-globin gene which in homozygous form causes sickle cell disease (SCD). No comparable studies have been done in African American children. We performed genome-wide association analyses of 482 African American children with documented pneumonia and 2048 African American controls using genotypes imputed from two reference panels: 1000 Genomes (1KG) (which contains rs334) and TOPMed (does not contain rs334). Using 1KG imputed genotypes, the most significant variant was rs334 (A allele (OR = 2.76 (2.21-3.74), p=5.9x10^-19); using TOPMed imputed genotypes the most significant variant was rs2226952, found in the β-globin locus control region (G allele (OR =2.14 (1.78-2.57), p = 5.1x10^-16). After conditioning on rs334, the most strongly associated variant in the β-globin locus was rs33930165, (allele T, 1KG: OR=4.09 (2.29-7.29), p=1.7x10^-6; TOPMed: OR=3.58 (2.18-5.90), p=4.7x10^-7), which as a compound heterozygote with rs334 A allele can cause SCD. To compare the power of different sample sets we developed a way to estimate the power of sample sets with different sample sizes, genotype arrays and imputation platforms. Our results suggest that in African American children the strongest genetic determinants of pneumonia are those that increase the risk of SCD.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142509498","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":"HCV- and HBV-mediated liver cancer converge on similar transcriptomic landscapes and immune profiles.","authors":"Elizabeth S Borden, Annika Jorgensen, Heini M Natri, Karen Taraszka Hastings, Kenneth H Buetow, Melissa A Wilson","doi":"10.1016/j.xhgg.2024.100373","DOIUrl":"10.1016/j.xhgg.2024.100373","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, and a large proportion is attributable to viral causes, including hepatitis B (HBV) and C viruses (HCV). The pathogenesis of viral-mediated HCC can differ between HBV and HCV, but it is unclear how much these differences influence the tumors' final molecular and immune profiles. Additionally, there are known sex differences in the molecular etiology of HCC, but sex differences have not been explored in the context of viral-mediated HCC. To determine the extent to which the viral status and sex impact the molecular and immune profiles of HCC, we performed differential expression and immune cell deconvolution analyses. We identified a large number of differentially expressed genes unique to the HBV or HCV tumor:tumor-adjacent comparison. Pathway enrichment analyses demonstrated that changes unique to the HCV tumor:tumor-adjacent tissue were dominated by changes in immune pathways. Immune cell deconvolution demonstrated that HCV tumor-adjacent tissue had the largest immune cell infiltrate, with no difference in the immune profiles within HBV and HCV tumor samples. Overall, this work demonstrates the convergence of HBV- and HCV-mediated HCC on a similar transcriptomic landscape and immune profile despite differences in the surrounding tissue.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476455","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}