HGG Advances最新文献

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 (DPSC) 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 to 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 (6 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 a 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 their ability to provide a comprehensive view of NSCLC mutation profiles. Here, we analyzed genome-wide screen data (including WGS and WES) from 1,874 NSCLC subjects to identify molecular subtypes, putative driver genes, and explore the effect of intrinsic and extrinsic factors on somatic mutation profiles. We showed that genome-wide screen data supports existing knowledge, such as the TP53:KRAS mutation co-occurrence pattern as a key distinctive feature, but does 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, EGFR), NSCLC subtype (14 genes including KRAS, NFE2L2, STK11), and smoking history (KRAS, CSMD3, 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.

Biallelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females all with a de novo single nucleotide variant within the start codon or the 5'UTR region of GLUL that truncate 17 amino acids of the protein product, including its critical N-terminal degron sequence, resulting in a disorder of abnormal glutamine synthetase stability and manifesting as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.

Most of the chemical energy that organisms rely on to support cellular function is generated through oxidative phosphorylation, a metabolic pathway in which electron donors, NADH and FADH, are oxidized through a series of successive steps to generate adenosine triphosphate. These redox reactions are orchestrated by a series of five protein complexes that sit within the mitochondrial membrane. Deficiency of cytochrome c oxidase, the fourth of these complexes, is a recognized cause of mitochondrial disease. COXFA4, encodes one of the protein subunits of cytochrome c oxidase and variants in COXFA4 have recently been reported in individuals with a range of symptoms. These can include feeding difficulties, poor growth, cardiomyopathy, Leigh or Leigh-like disease, and neurodevelopmental delay. Though these symptoms vary widely between individuals. Yet, a mechanistic understanding of the connection between COXFA4 loss and these varied disease manifestations is lacking. Using animal modeling in Xenopus, we explored the ramifications of coxfa4 loss of function on the early developing heart. We then conducted a hypothesis naive analysis of cellular gene expression in the context of COXFA4 deletion and discovered a downstream deficiency in the ornithine decarboxylase pathway. Small molecule-based modulation of the ornithine decarboxylase pathway in our model modified the extent of disease including improvement of cardiac function. Our findings point to a mechanism by which COXFA4 dysfunction leads to tissue specific disease.

CDO1 encodes a non-heme iron dioxygenase, which is involved in cysteine metabolism. While CDO1 has been proposed to be involved in multiple physiological processes, an association with congenital disease has yet to be well defined. This study presents detailed clinical and molecular information on three individuals with overlapping neurological features. All three individuals were found to have rare, conserved, de novo variants clustered in a conserved region of the CDO1 gene with no alternative genetic etiology identified. Features present in all three individuals included EEG abnormality or seizure, movement abnormalities, hypertonia, encephalopathy, severe microcephaly (-4SD below mean), growth failure, feeding difficulty, and abnormal brain morphology. Other common features included global developmental delay, sleep disturbance, contractures, cerebral palsy, hyperreflexia, hearing loss, and hypoxic respiratory failure. This study provides evidence supporting an association between de novo CDO1 missense variants and human neurological disease.

There is a scarcity of empirical data on the potential psychosocial and behavioral effects of returning genomic results for adult-onset conditions not medically actionable in pediatric patients. Potential harms include distress, discrimination, loss of future autonomy, or family functioning changes. The Pediatric Reporting of Genomic Results Study (PRoGRESS) explores outcomes of disclosing pediatric- and adult-onset genomic findings to families in an observational trial. Participants include adolescents (ages 11-17) with a genetic variant identified and returned through Geisinger's MyCode Genomic Screening and Counseling Program and their parents. This program involves returning pathogenic and likely pathogenic variants in a list of genes consistent with the American College of Medical Genetics and Genomics secondary findings list. Parents and adolescents with pediatric- and adult-onset results were invited to participate in interviews at 1 and 12 months post results disclosure. Here, we report the results of a qualitative analysis that included data from 25 participants with a known family history of a variant. Families generally had positive or neutral experiences with learning and adjusting to the results, and, on balance, felt it was beneficial to have the result. Previously proposed hypothetical concerns regarding disclosing adult-onset results to children were not reported in this cohort. Our findings provide guidance on supporting families in preparing for and adjusting to genomic results related to adult-onset conditions, particularly in care-delivery systems that are not designed to support families as the information becomes clinically relevant and provide evidence that longitudinal support may benefit families with an adult- or pediatric-onset result.

Genome-wide association studies have identified thousands of cardiovascular disease (CVD)-associated variants, with over 90% of them being mapped within the non-coding genome. Non-coding variants in regulatory regions of the genome, such as promoters, enhancers, silencers, and insulators, can alter the function of tissue-specific transcription factors (TFs) and their gene regulatory function. In this work, we used a computational approach to identify and test CVD-associated single nucleotide polymorphisms (SNPs) that alter the DNA binding of the human cardiac transcription factor GATA4. Using a gapped k-mer support vector machine (GKM SVM) model, we scored CVD-associated SNPs localized in gene regulatory elements in expression quantitative trait loci (eQTL) detected in cardiac tissue to identify variants altering GATA4-DNA binding. We prioritized four variants that resulted in a total loss of GATA4 binding (rs1506537 and rs56992000) or the creation of new GATA4 binding sites (rs2941506 and rs2301249). The identified variants also resulted in significant changes in transcriptional activity proportional to the altered DNA-binding affinities. In summary, we present a comprehensive analysis comprised of in silico, in vitro, and cellular evaluation of CVD-associated SNPs predicted to alter GATA4 function.

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10^-6) and outflow tract morphogenesis (p = 2.2 × 10^-5). Genes with NC DNVs (e.g., EFNB2, HEY2, and PITX2) interacted with NOTCH1 and FLT4 in a tight STRING protein-protein interaction (PPI) network. During the in vitro cardiac differentiation process, these noncoding candidate genes, which harbored potentially damaging regulatory NC DNVs, exhibited co-expression with NOTCH signaling genes and demonstrated dysregulated gene expression at various differentiation stages following NOTCH1 downregulation. In summary, our findings highlight a significant contribution of NC DNVs to TOF and suggest the presence of population genetic heterogeneity. Integrative analyses implicate dysregulation of NOTCH signaling, with converging influences from both coding and noncoding variants, in TOF within the Chinese population.