HGG Advances最新文献

'En bloc' inheritance of point mutations in adjacent genes has rarely been described. We have previously reported a family with severe, mostly early-lethal, Joubert syndrome (JBTS) with early-onset severe retinal dystrophy (EOSRD) and polycystic kidney disease (PKD), which had then been attributed to a homozygous pathogenic missense variant, p.(Arg106Pro), in the ciliary POC1B gene. Because this and other POC1B variants were in subsequent studies only reported in patients with non-syndromic childhood or early-adult-onset macular dystrophy, we now reassessed our index patient by long-read HiFi whole-genome sequencing (LR-WGS). We identified a homozygous deep-intronic variant, c.2818-657T>G, in CEP290, a JBTS/Meckel syndrome-associated gene on chromosome 12q21, only 1.28 Mb from the N-terminus of POC1B. cDNA analysis revealed aberrant splicing with the frame-shifting inclusion of 37 bp from CEP290 intron 25, predicting loss of CEP290 function. EOSRD and PKD can fully be ascribed to this CEP290 variant whose effect outshines the "background" non-syndromic POC1B retinopathy and co-segregates with the severe syndromic phenotype. Our novel findings in this family no longer justify POC1B as a JBTS gene. This co-inheritance of two ciliopathies, with the clinically decisive variant hidden deep in an intron, exemplifies the importance of WGS for achieving the complete diagnosis in challenging cases.

Functional genomic annotations can improve polygenic scores (PGS) within and between genetic ancestry groups. While general annotations are commonly used in PGS development, tissue- and cell type-specific annotations derived from open chromatin and gene expression experiments may further enhance PGS for cardiometabolic traits. We developed PGS for 14 cardiometabolic traits in the UK Biobank using SBayesRC. We integrated GWAS summary statistics from FinnGen and GLGC with three annotation sources: i) baseline-LD model v2.2 (general annotations), ii) cell type-specific snATAC-seq peaks, and iii) tissue-specific eQTLs/sQTLs. We created PGS using two EUR LD reference panels (1.2M HapMap3 variants and 7M imputed variants). Tissue- and cell type-specific annotations showed stronger heritability enrichment than baseline-LD annotations on average, particularly coronary snATAC-seq peaks and fine-mapped eQTLs. Without annotations, HapMap3 and 7M variant PGS performed similarly. However, with all annotations, 7M variant PGS outperformed HapMap3 variant PGS (8% average increase in relative performance in EUR). Compared to using no annotations, modeling baseline-LD annotations improved performance by 5% for HapMap3 and 11% for 7M variant PGS, while modeling all annotations yielded improvements of 5% and 13%, respectively. Although annotations provided greater relative improvement for cross-ancestry prediction, they did not decrease the disparity in PGS performance between genetic ancestry groups. Functional annotations improved PGS for cardiometabolic traits. Despite strong heritability enrichment, tissue- and cell type-specific snATAC-seq and eQTL annotations provided marginal performance gains beyond general genomic annotations.

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using the MADCaP Array. We first tested how genetic predictions of baldness generalize from Europe to Africa and found that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness generalized poorly from European to African populations. Subsequently, we conducted an African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for age at recruitment, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10^-5, r² < 0.2). Most baldness associations were autosomal, and the X chromosome does not appear to have a large impact on baldness in African men. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, within the limits of statistical power, we did not find evidence that continental differences in the genetic architecture of baldness are due to Neanderthal introgression. While most loci that are associated with androgenetic alopecia do not have large iHS or F_ST statistics, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how population genetic differences contribute to the limited portability of polygenic predictions across ancestries.

To date, the KCTD10 gene (MIM# 608726) has not been definitively associated with a human disease, although studies in animal models suggest that it plays a role in embryonic development. We have identified multiple unrelated individuals with de novo missense variants and overlapping phenotypes including congenital heart anomalies and congenital anomalies in other organ systems in our internal database. This report includes a detailed description of the genotype and phenotype for two consented individuals and aggregate data of additional individuals who were not available for case-specific publication. Based on the data presented here, we propose that damaging de novo missense KCTD10 variants are associated with an autosomal dominant phenotype including cardiac and other congenital anomalies. We encourage additional studies to further characterize this condition and identify a mechanism for disease.

Haploinsufficiency of FBXO11, encoding a ubiquitin ligase complex subunit, is associated with a variable neurodevelopmental disorder. So far, the underlying nervous system-related pathomechanisms are poorly understood, and specific therapies are lacking. Using a combined approach, we established an FBXO11-deficient human stem cell-based neuronal model using CRISPR-Cas9 and a Drosophila model using tissue-specific knockdown techniques. We performed transcriptomic analyses on iPSC-derived neurons and molecular phenotyping in both models. RNA sequencing revealed disrupted transcriptional networks related to processes important for neuronal development, such as differentiation, migration, and cell signaling. Consistently, we found that loss of FBXO11 leads to neuronal phenotypes such as impaired neuronal migration and abnormal proliferation/differentiation balance in human cultured neurons and impaired dendritic development and behavior in Drosophila. Interestingly, application of three different proteasome-activating substances could alleviate FBXO11-deficiency-associated phenotypes in both human neurons and flies. One of these substances is the long-approved drug Verapamil, opening the possibility of drug repurposing in the future. Our study shows the importance of FBXO11 for neurodevelopment and highlights the reversibility of related phenotypes, opening an avenue for potential development of therapeutic approaches through drug repurposing.

Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who have had JIA continue to have active disease and have developed functional limitations. Medication side effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA (when compared to healthy control subjects). Of the 28 candidates, the strongest new target to emerge was homeodomain-interacting protein kinase 1 (HIPK1), which suppresses T cell activation and is within the PTPN22 locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls, and PML, a known coregulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by a spectrum of symptoms, including developmental delay, intellectual disability, and increased risk of autism. PWS is an imprinting disorder caused by the loss of paternal expression of critical genes in the 15q11.2-q13 region, including MAGEL2, SNRPN/SNURF, and SNORD116. PWS patients often suffer from various sleep disorders, including sleep-disordered breathing and central hypersomnolence. Mouse models of PWS also exhibit disruptions in circadian rhythms and sleep. In cultured cells, Magel2 was shown to regulate the expression of Bmal1 and Per2, two core clock genes involved in the circadian rhythm regulatory process. Here, we investigated the circadian clock function in neurons derived from dental pulp stem cells (DPSCs) of PWS patients and neurotypical controls. To study the circadian rhythms of PWS patients in vitro, we introduced the Per2 promoter-driven luciferase reporter (Per2:luc) to these DPSC cell lines to assess their circadian rhythm by bioluminescence. These Per2:luc cells were differentiated for 4 weeks to mature neuronal reporter cell lines, followed by kinetic measurements of luciferase activity over several days. We observed significant differences in circadian period length between PWS neurons and controls. Moreover, treatment with the small molecule longdaysin effectively lengthened the period length of PWS neurons with a shorter period length, as anticipated based on the mechanism of action of this compound. This work lays the foundation for a deeper understanding of PWS pathophysiology and represents a critical first step toward developing high-throughput assays for drug discovery targeting circadian and sleep dysfunction in PWS.

Genome-wide association studies (GWASs) for atopic dermatitis (AD) have uncovered 81 risk loci in European participants; however, translating these findings into functional and therapeutic insights remains challenging. We conducted a transcriptome-wide association study (TWAS) in AD leveraging cis-eQTL data from sun exposed (n = 517), non-sun exposed skin (n = 602) and whole blood (n = 670) tissues and the latest GWAS of AD in Europeans (n = 864982). We implemented the OTTERS pipeline that combines polygenic risk score (PRS) techniques accommodating diverse assumptions in the architecture of gene regulation. We also used differential expression meta-analysis and co-expression networks (n = 186) to characterize the transcriptomic landscape of AD. We identified 176 gene-tissue associations covering 126 unique genes (53 previously unreported). Most TWAS risk genes were identified by adaptive PRS frameworks, with non-significant differences compared with clumping and thresholding approaches. TWAS risk genes were enriched in allergic reactions (e.g., AQP7, AFF4), skin barrier integrity (e.g., ACER3), and inflammatory pathways (e.g., TAPBPL). By integrating co-expression networks of lesional AD skin, we identified 16 hub genes previously identified as TWAS risk genes (six previously unreported) that orchestrate inflammatory responses (e.g., HSPA4) and keratinization (e.g., LCE3E, LCE3D), serving as potential drug targets through drug-gene interactions. Consistent associations between all analyses were reported for FOSL1 and RORC. Collectively, our findings provide additional risk genes for AD with potential implications in therapeutic approaches.

PHACTR4 is proposed to play a role in embryonic development but has yet to be associated with human disease. Here, we report the detailed clinical features of two individuals for whom molecular diagnostic testing was undertaken at a large diagnostic laboratory and who were found to harbor rare, damaging de novo missense variants in the conserved RPEL3 domain of PHACTR4. We also present aggregate information on additional individuals in whom missense variants in the same PHACTR4 gene region were detected. All presented with overlapping phenotypes. Features present in at least half of these individuals included cleft palate, ophthalmologic abnormalities, hearing impairment, dysmorphic facial features, digital anomalies, renal/urinary anomalies, growth delay, microcephaly, abnormal brain imaging, and neurodevelopmental abnormalities; some individuals had additional unique findings as well. The proposed cellular function of PHACTR4 and information from related genes with variants in an RPEL domain suggest that PHACTR4 is a promising candidate gene for human disease. We hope that this report will promote additional research interest in the PHACTR4 gene and lead to the publication of additional cases, to potentially establish a causative relationship and to further delineate the phenotypic and variant spectrum of a PHACTR4-related disorder.

Non-small cell lung cancer (NSCLC) is driven by a diverse array of somatic mutations. The vast majority of literature on NSCLC is based on targeted assays or small sample sizes, limiting the ability to provide a comprehensive view of NSCLC mutation profiles. Here, we analyzed genome-wide screen data (including whole genome sequencing and whole exome sequencing) from 1,874 NSCLC subjects to identify molecular subtypes and putative driver genes and to explore the effect of intrinsic and extrinsic factors on somatic mutation profiles. We showed that genome-wide screen data support existing knowledge, such as the TP53:KRAS mutation co-occurrence pattern as a key distinctive feature, but do not reveal additional broad molecular subtypes. In contrast, we demonstrated that low-frequency molecular subtypes or potential driver genes continue to be identified. Using driver gene identification algorithms, we found 50 potential driver genes including ANG, CDK10, CTDSP2, HOXA5, RBP4, and SPHK2, which show evidence of positive selection in NSCLC. Finally, we provided insights into the intrinsic and extrinsic covariates associated with the NSCLC somatic mutation landscape, while confirming associations with ethnicity (TP53 and EGFR), NSCLC subtype (14 genes including KRAS, NFE2L2, and STK11), and smoking history (KRAS, CSMD3, and TP53), we dismissed gene-level associations with sex when other covariates are controlled for. The results presented here represent a concise up-to-date summary of variation in the somatic mutation landscape and carry importance for NSCLC geneticists, medical practitioners, and drug discovery scientists.