HGG Advances最新文献

The TOMM40'523 poly-T repeat polymorphism (rs10524523) has been associated with cognitive decline and Alzheimer's disease (AD) progression. Challenges in processing whole-genome sequencing (WGS) data traditionally require additional PCR and targeted sequencing assays to genotype these polymorphisms. We introduce a computational pipeline that integrates multiple short tandem repeat (STR) detection tools in an ensemble machine learning model using XGBoost. Using a sample of 1,202 participants from 4 cohort studies, we benchmarked our method against PCR-based measures. Our ensemble model outperformed individual STR tools, improving repeat length estimation accuracy (R² = 0.92) and achieving an accuracy rate of 93.2% compared with PCR-derived genotypes. Additionally, we validated our WGS-derived genotypes by replicating previously reported associations between TOMM40'523 variants and cognitive decline. Our computational genotyping tool is a scalable and reliable alternative to PCR-based assays, enabling broader investigations of TOMM40 variation in studies with WGS data.

Disease-causing variants with penetrance that is lower than the average expected for a given gene complicate classification, even when using gene-specific guidelines. For TP53, a gene associated with some of the highest cancer risks, even reduced penetrance disease-predisposition variants remain clinically actionable. We conducted a review of ClinVar submissions to identify TP53 variants flagged as having reduced penetrance by genetic testing laboratories and analyzed functional, bioinformatic, immunogenicity, frequency, and clinical features of these variants compared with standard pathogenic and benign variants. Our findings show that reported reduced penetrance TP53 variants are more likely to exhibit intermediate functional activity in multiple assays and are predicted as deleterious with bioinformatic tools, though with lower scores than pathogenic variants. These variants also have a higher population frequency than pathogenic variants, and heterozygotes tend to manifest disease later in life, suggesting a need for refined clinical criteria to better capture attenuated Li-Fraumeni syndrome phenotypes. Finally, by applying a random forest prediction model to all TP53 uncertain or conflicting variants in ClinVar, we identified 106 additional variants with potential reduced penetrance.

We investigated colon cancer genomics and microenvironmental features in the Appalachian Kentucky population, a group with the highest incidence of colon cancer in the United States. We assessed two inter-related risk factors for colon cancer (obesity and abnormal gut bacterial microbiome) and their genetic associations within this population. To evaluate potential unique characteristics of the high-incidence cohort, we compared 99 propensity-matched colon cancer tumors from Appalachian Kentucky patients to 95 non-Appalachian patient tumors to evaluate driver mutations, differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, immune cell populations, and microbiomes in an obesity context. Our comparison identified significant population-specific DEGs and differences in COSMIC signature frequencies, KEGG pathway regulation, pro-carcinogenic immune cell features, microbiome species, and obesity-associated inflammatory and metabolic responses between the cohorts. The findings offer generalizable implications deriving from Appalachian Kentuckians while highlighting the critical importance of population-based studies in colon cancer research.

Whole-genome sequencing (WGS) as a diagnostic test offers children suspected of having a rare genetic condition and their families the best direct path toward securing a precise genetic diagnosis (PrGD). Yet, a limited supply and inequitable access to genetic services are impediments to realizing the benefits of a PrGD. Such access disparities might be due to a range of structural and social determinants that manifest in interactions, or the lack thereof, between families, providers, and institutions. Semi-structured key informant interviews (n = 19) were conducted with neonatologists and neurodevelopmental clinic providers (NDV providers) who referred families to the SeqFirst study to identify barriers and inform strategies to improve equitable access to a PrGD via WGS. Overall, neonatologists and NDV providers were enthusiastic about offering WGS to their patients and families despite different contexts of medical care. Providers cited several considerations that influenced their introduction of WGS and genetic testing to families, including their perceptions of families' capacity, readiness, and distrust and the establishment of sufficient provider-family rapport. These considerations influenced providers' timing and introduction of genetic testing and WGS to families. Together, these findings suggest that providers' perceptions of families may result in delayed introduction of WGS.‬ Despite enthusiasm for early WGS across medical subspecialties, providers' perceptions of families and their social contexts highlight both challenges and opportunities in the implementation of WGS to promote and maximize equitable access.

We developed an imputation panel for Alzheimer disease (AD) and related dementias (ADRD) using 15,958 whole-genome sequencing (WGS) samples from the Alzheimer Disease Sequencing Project. Recognizing the importance of associations between structural variants (SVs) and AD and their underrepresentation in existing public reference panels, our panel uniquely integrates single-nucleotide variants (SNVs), short insertions or deletions (indels), and SVs. This panel enhances the imputation of rare variants underlying disease susceptibility onto genotype array data, offering a cost-effective alternative to WGS while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominally significantly associated with AD that are absent in the TOPMed-r2 panel and identified one genome-wide significant (p < 5 × 10^-8) and three suggestive significant (p < 1 × 10^-5) AD-associated SVs. These findings provide the other insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.

CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aimed to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical phenotypes using standardized measures, and explore potential genotype-phenotype correlations. In this cross-sectional cohort study, individuals diagnosed with CTNNB1 neurodevelopmental syndrome underwent structured interviews using standardized scales to evaluate motor skills, speech, communication, feeding abilities, visual function, neurodevelopment, and psychopathology. Genetic variants were analyzed, and, in a subset of cases, the impact of β-catenin variants on the Wnt/β-catenin signaling pathway was assessed. Across the 127 included participants (mean age, 70 months; range, 7-242 months) from 20 countries, we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function. Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect. One missense variant demonstrated a gain-of-function effect. Dominant-negative variants were not clearly associated with a distinct phenotype; however, those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties. This study describes the genetic, functional, and phenotypic characteristics in individuals with CTNNB1 neurodevelopmental syndrome. Further investigation into the genotypic and phenotypic characteristics of this syndrome and their interrelationships is essential to deepen our understanding of the disorder and inform the development of targeted therapies.

Rare diseases pose a significant public health challenge, particularly in underserved regions such as China, where genomic diagnostic services and post-diagnosis management remain limited. This study assessed the effectiveness of a rare disease screening program in Changsha, China, which enrolled 85,391 couples between January 2022 and June 2023. Among these participants were 1,414 suspected high-risk couples undergoing genetic testing, with 562 found to be at high risk of having a child with a rare disease, yielding a positive rate of 39.75%. Reproductive interventions were implemented for 319 families, successfully preventing rare disease-affected births in 141 cases. Diagnostic findings informed reproductive decision-making in 25.09% of cases and altered fertility plans in 32.74%. Machine learning analysis further revealed that participation in a parent-offspring trio and a positive family history significantly increased diagnostic likelihood, while singleton recruitment and a negative history were associated with lower diagnostic success. This pilot program highlights the value of integrating genetic diagnostics with reproductive interventions, offering a replicable model for rare disease prevention and management.

Genetic factors play an important role in prostate cancer (PCa) development with polygenic risk scores (PRS) predicting disease risk across genetic ancestries. However, there are few convincing modifiable factors for PCa and little is known about their potential interaction with genetic risk. Our study explores the role of neighborhood socioeconomic status (nSES)-and how it may interact with PRS-on PCa risk. We analyzed incident PCa cases and controls of European (cases = 5,960; controls = 93,990) and African (cases = 109; controls = 1,226) ancestry from the UK Biobank cohort. Using the English indices of deprivation, a set of validated metrics that quantify lack of resources within geographical areas, we performed logistic regression to investigate the main effects and interactions between nSES deprivation and genetic susceptibility to PCa, represented by a multi-ancestry PRS comprised of 269 genetic variants. The PRS was associated with PCa in the European (OR = 2.04; 95% confidence interval [CI], 2.00-2.09; p = 5.34 × 10^-807) and African (OR = 1.35; 95% CI, 1.16-1.58; p = 1.05 × 10^-4) ancestries. Additionally, nSES deprivation indices were inversely associated with PCa: employment, education, health, and income. From this, we suspect that PRS, through biological mechanisms, and nSES deprivation, likely through differences in screening, are associated with PCa, but act independently of each other. Our findings suggest that genetic factors and social determinants of health measured by neighborhood socioeconomic status do not synergistically increase risk of PCa.

Risk-based approaches offer promise for enhancing early detection of prostate cancer. Polygenic risk scores (PGSs) have emerged as a potential approach for risk stratification, though their performance varies by population. We evaluated nine PGSs (four existing, five new) for predicting 5-year prostate cancer risk across three international population-based prospective cohorts: UK Biobank (UKB), the Australian QSkin Sun and Health Study (QSkin), and Melbourne Collaborative Cohort Study (MCCS). We analyzed UKB European-ancestry (n = 184,010), South-Asian-ancestry (n = 5,097), and African-ancestry (n = 3,193), QSkin European-ancestry (n = 6,791), and MCCS European-ancestry (n = 1,809) male participants. We estimated age-specific 5-year prostate cancer risks (from population data) and PGS-adjusted risks (age-specific risks multiplied by PGS-based relative risks). Predictive performance was assessed using discrimination (AUC) and calibration. PGS significantly enhanced 5-year risk prediction over age alone, particularly for European ancestry (AUC increase 0.05-0.12, p < 10^-6). PGS performance was consistent across European-ancestry men in Australian and UK cohorts, and by pre-baseline prostate-specific antigen tests and family history in UKB. No single PGS outperformed others across all cohorts and ancestry groups. As an illustrative example for potential risk stratification, for a leading PGS in both Australian cohorts, we estimated the population-average 5-year risk at age 50 was reached 5 years earlier by individuals with 20% highest PGS451 and 5 years later by those with 20% lowest PGS451. In conclusion, rigorous analyses with consistent results from international cohorts support the potential of PGS to improve 5-year prostate cancer risk prediction. In the future, PGS may be improved further to enhance performance in diverse populations.

Creatine phosphate is a high-energy molecule essential for the normal functioning of highly metabolically active organs and tissues. SLC6A8 encodes the only known creatine transporter in humans (CRT1); pathogenic variants result in a neurophenotype that includes intellectual disability, seizures, and autistic-like behaviors. Due to the importance of creatine phosphate in normal brain function, we compared the amino acid sequence among a group of terrestrial mammals and zebrafish. Finding high interspecies invariance, we (1) sought to quantitatively assess the effect of a number of existing disease-causing SLC6A8 variants on in vitro creatine uptake, comparing variant type/location, along with (2) the reported effect of missense variants on severity classification. Creatine uptake in the pathogenic variants studied demonstrated that the vast majority had a profound effect on uptake; only 1, in a peripheral extracellular loop, had a moderately reduced effect. Of the missense variant analysis, those occurring in C and N termini were tolerated more, while variants in transmembrane domains tended to more likely affect function. While the high degree of amino acid conservation across terrestrial mammals underscores its evolutionary importance, together with the variant analysis, these findings provide a framework for understanding genotype-phenotype correlations in variants of CRT1 and highlight the critical functional constraints.