Human Genetics最新文献

The genetic etiology of Fuchs Endothelial Corneal Dystrophy (FECD) is not yet fully elucidated. While the disease is widespread and the leading indication for corneal transplantation in the Western world, the concurrent shortage of corneal transplants underscores the urgent need for further research into the underlying mechanisms. Such investigations could enable the development of innovative therapeutic strategies. Therefore, we aimed to verify candidate genes previously identified and sought after novel variants in the German population. Undertaking a genome wide association study (GWAS) using the Axiom™ Precision Medicine Diversity Array on 157 FECD cases and 309 controls, followed by pathway enrichment analysis, we were able to confirm the significance of the TCF4 locus (rs613872, p = 8.0 × 10^- 23, OR = 8.60, h² = 0.72) and identified a range of novel variants. Further fine-mapping highlighted novel candidate SNPs, such as on chromosome 5 in the SEMA6A gene (rs153643, p = 3.1 × 10^- 9, OR = 2.75, h² = 0.30), and on chromosome 19 in the DNAJC19P3 gene (rs62117964, p = 3.3 × 10^- 8, OR = 3.61, h² = 0.29). SEMA6A gene is involved in apoptotic pathways and cytoskeletal remodeling, making it an interesting candidate gene for further investigations as a potential therapeutic target. Furthermore, several variants were identified in lncRNAs, which presumably influence the expression of nearby protein-coding genes. For example, LOC105372130, which is associated with corneal hysteresis and corneal resistance factor, may influence the expression of TCF4.

Hereditary spherocytosis (HS) is a common form of haemolytic anaemia caused by defects or deficiencies in genes encoding erythrocyte membrane proteins, such as ANK1, SPTB, SLC4A1, EPB42, and SPTA1. Among these, ANK1 and SPTB mutations are the most frequent causes of HS worldwide. This study analysed 53 Indian HS patients, identifying 33 novel and 12 previously reported SPTB variants using targeted next-generation sequencing (t-NGS). The identified SPTB variants included frameshift (28%), missense (24%), nonsense (44%), and splicing (4%) types, with nonsense variants being the most common. These nonsense variants typically result in truncated proteins. The variants were widely distributed across the gene, with the highest density observed in the spectrin repeats and ankyrin-binding domain, while no variants were found in the tetramerization domain. All identified SPTB variants exhibited heterozygous inheritance, consistent with an autosomal dominant inheritance pattern of the gene causing HS. One patient, however, carried compound heterozygous variants, leading to severe anaemia, and five patients had de novo SPTB variants. This study expands the spectrum of SPTB variants, enhances the understanding of spectrin-related molecular defects, establishes genotype-phenotype correlations, and provides valuable insights for laboratories developing genetic tests for HS. The high number of identified variants highlights the importance of advanced technologies like NGS for accurate molecular diagnosis in HS disorder. This approach not only supports clinical diagnostics but also aids in family counseling for improved management of HS.

Currently, new research projects aim to develop prognostic models that more accurately predict the age of onset and progression of disease for adult-onset autosomal dominant neurodegenerative diseases that lack disease-modifying treatments. While such predictions can be important for medical research and valuable in clinical practice, the perspectives of mutation carriers on receiving onset and progression predictions have not yet been explored. In this Dutch qualitative interview study, conducted between May and August 2023, the preferences, views, and concerns of 25 asymptomatic mutation carriers of Huntington's Disease, Spinocerebellar Ataxia type 1, or Spinocerebellar Ataxia type 3 regarding onset and progression predictions were examined. Reasons for wanting to receive onset and progression predictions included life planning, preparing for the disease, informing family members, and reducing uncertainty and hypervigilance. Reasons against included concerns about negative psychological effects, the expectation of similar disease progression as family members, and a preference for receiving progression information at a later stage. Most participants were open towards disclosure of onset predictions but more hesitant regarding receiving progression information. The reasons expressed and the preferred predicted age ranges varied among age groups, and some differences in preferences were observed between the three diseases. These findings may guide the development and responsible implementation of such prognostic models and can support healthcare professionals in the counselling of mutation carriers of adult-onset genetic neurodegenerative diseases.

In the last decade the increasing use of germline genetic testing has led to frequent discoveries of secondary findings (SF) in hereditary cancer (HC) genes. Disclosure and clinical management of such findings are still not clearly defined and raise many ethical, clinical, and practical questions. This systematic review is focused on frequency of reported SF in HC genes across different populations as well as summarizing current guidelines, recommendations, and actual clinical practice about reporting and managing SF in HC genes. A systematic literature search according to the PRISMA guidelines was performed on the electronic database PubMed from inception to June 2024. 30 research papers involving almost 150,000 patients were reviewed. The reported frequencies of SF in HC genes varied between 0.4 and 3.1%. The majority of patients agreed to receive SF for medically actionable genes. Management and surveillance of patients after disclosure of SF in HC genes were rarely reported, but the limited data show no regret of receiving such results as well as diagnoses of early-stage cancer in patients participating in recommended surveillance programs related to SF. A substantial number of carriers of highly penetrant pathogenic variants in HC genes is discovered by reporting SF after germline genetic testing with next-generation sequencing. Additional information about the impact of SF disclosure on individuals and health care systems is needed to optimize the integration of SF into clinical care.

Reliable prediction of pathogenic variants plays a crucial role in personalized medicine, which aims to provide accurate diagnosis and individualized treatment using genomic medicine. This study introduces PRP, a pathogenic risk prediction for rare nonsynonymous single nucleotide variants (nsSNVs), including missense, start_lost, stop_gained, and stop_lost variants. PRP was designed to provide robust performance and interpretable predictions using thirty-four features across four categories: frequency, conservation score, substitution metrics, and gene intolerance. Five machine-learning (ML) algorithms were compared to select the optimal model. Hyperparameter optimization was conducted using Optuna, and feature importance was analyzed using Shapley Additive exPlanations (SHAP). PRP used ClinVar data for training and evaluated performance using three independent test datasets and compared it with that of twenty other prediction tools. PRP consistently outperformed state-of-the-art tools across all eight performance metrics: AUC, AUPRC, Accuracy, F1-score, MCC, Precision, Recall, and Specificity. In addition to achieving high sensitivity and high specificity without overestimating the number of pathogenic variants, PRP demonstrates robustness in predicting rare variants. The datasets and codes used for training and testing PRP, along with pre-computed scores, are available at https://github.com/DNAvigation/PRP .

Consanguineous marriages are common in many worldwide human populations, and the biological consequences for offspring can be relevant at the biomedical level. The current genomic revolution displayed through genome-wide studies is challenging the paradigm in the analysis of consanguinity. Here, we analyzed genomic inbreeding patterns in human populations located at the western edge of the Mediterranean region (Iberia and Morocco). Runs of Homozygosity (ROH) (autozygosity fragments) were identified in 139 autochthonous individuals originating from southern Iberia and Morocco via microarray data. All individuals analyzed carried at least one ROH in their genomes. The genomic inbreeding coefficient (F_ROH) and the presence of ROH islands (ROHi) revealed interesting patterns in the target populations as well as in the rest of the Mediterranean basin. Moroccan Berbers presented signals of recent inbreeding, relying on high coverage of long ROH (> 5 Mb) and F_ROH. The location and structure of ROHi among people in the western Mediterranean could be interpreted as a signature of common genetic links across the Strait of Gibraltar. We found a significant enrichment of some relevant biological functions in the estimated ROHi hotspots associated with the immune system and chemosensation. Genomic inbreeding approaches allow us to understand past population histories and can be used as a proxy to scan the genome in search of selection signals.

Genetic variants in two major histone H3K36 methyltransferases, NSD1 and SETD2, have been identified in patients with neurodevelopmental disorders. We examined the genetic nature of these disease-relevant variants and studied genotype-phenotype correlations using publicly available patient cohorts. To further investigate roles of Nsd1 and Setd2 in brain development, we generated mouse models with conditional knockout of Nsd1 and Setd2 in neuroepithelial cells using the Sox1-cre. Our results showed that conditional Nsd1 knockout mice were viable but exhibited reduced brain size and thinning of neocortex, while Setd2 knockout led to neonatal death with intracerebral hemorrhage and vascular abnormalities. Together, our study demonstrates new roles of Nsd1 and Setd2 in brain development.

The study aims to enhance the efficiency of the genetic variant curation process at the Hong Kong Genome Institute by developing a Semi-Automated Bespoke Cohort Analysis Workflow (S-BCAW) for patients with, or suspected to have, retinitis pigmentosa (RP) in the Hong Kong Genome Project (HKGP), leveraging advances in next-generation sequencing (NGS). A comparative analysis involving 79 RP patients was conducted using both the conventional manual workflow and the novel S-BCAW, which integrates initial filtering and variant classification based on ACMG guidelines, followed by detailed manual review. The diagnostic yields from both methods were identical, but the bespoke workflow reduced analysis time by approximately 60% (1.5 h/sample). This efficiency increase resulted from automated application of ACMG rules and systematic aggregation of supportive data, including disease-specific information. The study reports 25 positive cases with a diagnostic yield of 32%, including three novel variants. The S-BCAW significantly improves efficiency, helping to end the diagnostic odyssey for patients in the HKGP. This approach facilitates rapid assessment of variant pathogenicity, enhancing the feasibility and timeliness of NGS technology for clinical applications, especially in urgent scenarios.

Transfer RNA-derived small RNAs (tsRNAs) have emerged as potential biomarkers of various human diseases. However, the clinical utility and biological functions of tsRNA in acute coronary syndrome (ACS) remain poorly understood. To investigate this, we performed high-throughput small RNA sequencing on peripheral blood monocyte cells (PBMCs) from 24 ACS patients and 12 healthy controls. Our analysis revealed distinct and characteristic expression patterns of tsRNAs in response to ACS, highlighting their potential as disease signatures in human PBMCs. Differentially expressed tsRNAs were validated using RT-qPCR in two independent case-control sets. Among these, tRF-Gly-GCC-06 was significantly upregulated in volunteers with unstable angina (UA) and acute myocardial infarction (AMI) (p < 0.05) and showed a statistically significant positive correlation with the Gensini score (r = 0.353, p < 0.001). Moreover, this tsRNA was independently associated with an increased risk of ACS after adjusting for conventional cardiovascular risk factors (odds ratio (OR) = 1.58, 95% confidence interval (CI): 1.37-1.83, p < 0.001). A series of functional studies showed that tRF-Gly-GCC-06 significantly facilitated macrophage proliferation and migration and modulated inflammation-related gene expression in vitro. This study identified a novel functional gene associated with ACS, tRF-Gly-GCC-06, as a potential clinical biomarker and therapeutic target.

Hereditary ataxia (HA) is a heterogeneous group of complex neurological disorders, which represent a diagnostic challenge due to their diverse phenotypes and genetic etiologies. Next-generation sequencing (NGS) has revolutionized the field of neurogenetics, improving the identification of ataxia-associated genes. Notwithstanding, repeat expansions analysis remains a cornerstone in the diagnostic workflow of these diseases. Here we describe the molecular characterization of a consecutive single-center series of 70 patients with genetically uncharacterized HA. Patients' samples were analyzed for known HA-associated repeat expansions as first tier and negative ones were analyzed by whole exome sequencing (WES) as second tier. Overall, we identified pathogenic/likely pathogenic variants in 40% (n = 28/70) and variants of unknown significance (VUS) in 20% (n = 14/70) of cases. In particular, 10 patients (14.3%, n = 10/70) presented pathogenic repeat expansions while 18 cases (30%, n = 18/60) harbored at least a single nucleotide variant (SNV) or a copy number variant (CNV) in HA or HSP-related genes. WES allowed assessing complex neurological diseases (i.e., leukodystrophies, cerebrotendinous xanthomatosis and atypical xeroderma pigmentosum), which are not usually referred as pure genetic ataxias. Our data suggests that the combined use of repeat expansion analysis and WES, coupled to detailed clinical phenotyping, is able to detect the molecular alteration underpinning ataxia in almost 50% cases, regardless of the hereditary pattern. Indeed, NGS-based tests are fundamental to acknowledge novel HA-associated genes useful to explain the remaining wide fraction of negative tests. Nowadays, this gap is problematic since these patients could not benefit from an etiological diagnosis of their disease that allows prognostic trajectories and prenatal/preimplantation diagnosis.