Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are diseases provoked by mutations in multifunctional proteins that are involved in DNA repair. DNA-repair deficiency explains the high cancer incidence of XP, whereas cancer-free CS, characterized by growth retardation, neurological degeneration, and premature aging does not present as a classical DNA-repair deficiency disorder. Here, we compared a severe combined XP/CS case provoked by XPG-mutation with an XP "only" patient cell line caused by mutation in the same XPG gene to carve out the pathogenic cellular disturbances that provoke CS. We identified RNA polymerase I transcription and rRNA maturation defects, a highly phosphorylated eukaryotic initiation factor 2 alpha (eIF2alpha), and a shift from cap- to internal ribosomal entry site (IRES) translation, indicating an activated integrated stress response in CS. Disturbances in ribosomal biogenesis and translational control might thus contribute to the development of CS.

Dyslipidemia is an important risk factor for cardiovascular diseases and can result from genetic and environmental influences. Most genome-wide association studies (GWAS) have been conducted in European populations, limiting our understanding of polymorphisms involved in lipid levels in admixed populations such as Brazilians. Therefore, this study aimed to identify genetic variants associated with lipid traits and develop polygenic risk scores (PRS) for dyslipidemia prediction in a large cohort of Brazilians. We performed GWAS of lipid phenotypes using 19,016 Brazilian individuals previously genotyped with SNP array and with available biochemical lipid measurements. After quality control and imputation, GWAS analyses were conducted separately for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL cholesterol (non-HDL-C). Trans-ancestry PRS were constructed using PRS-CSx. A set of 161 lead genome-wide significant SNPs were identified across lipid traits, including 62 previously reported in different populations, and many others representing potential novel associations for TC and TG. PRS models showed consistent associations with lipid levels, with increasing prevalence of elevated TC, LDL-C, non-HDL-C, and TG across higher PRS deciles. The area under the curve (AUC) values ranged from 0.62 to 0.66 across traits, with the highest performances for TC, non-HDL-C and TG. This study provides new insights into the genetic architecture of lipid traits in an admixed Brazilian population. Our findings underscore the relevance of conducting GWAS in diverse populations, support the use of PRS for risk stratification and prevention, and point to novel targets for drug development.

Neonatal diabetes mellitus (NDM) typically presents within the first 6 months of life and generally lacks islet autoantibodies. Genetic elucidation of NDM is a prime example of precision medicine in diabetes. However, no published genetic data exist for NDM in Thailand. We aimed to assess the genetic etiology of Thai NDM using whole exome sequencing (WES). We enrolled 14 Thai patients with NDM and measured GAD65, IA-2, and ZnT8 autoantibodies. We then performed WES and analyzed 43 NDM-related genes to identify causative variants. All subjects tested negative for the three islet autoantibodies. Eight harbored variants in well-established NDM genes (KCNJ11 [n = 5], ABCC8 [n = 1], INS [n = 2 in identical twins]). Two patients with KCNJ11 variants (rs80356616: p.Val59Met and rs8035661: p.Arg50Gln) achieved excellent glycemic control on sulfonylureas, illustrating precision therapy. The remaining six carried pathogenic variants in genes associated with monogenic diabetes, including LRBA, EIF2AK3, DOCK8, WFS1, GATA6, CISD2/SLC9B1, and COQ2. This is the first report on the genetic etiology of NDM in Thailand. WES is an effective approach to identifying variants in this rare diabetes subtype. Larger cohort studies are needed to determine the true prevalence of NDM in Thailand.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00439-025-02815-0.

The SLC6A14 gene on chromosome X modifies disease presentation in individuals with cystic fibrosis (CF). Population studies have revealed distinct proximal and distal SNP clusters associated with gastrointestinal and lung phenotypes, respectively. Given the co-localization of cis-eQTLs within the corresponding associated chromosomal regions, where less SLC6A14 expression aligns with improved phenotypic outcomes, we sought to understand the SNP contributions to SLC6A14 expression regulation. Using reporter gene assays, we show that the proximal cluster, aligning with pancreas eQTLs, provides variation in promoter activity that is allele-dependent. The more expansive distal cluster, aligning with primary nasal cell eQTLs, was surveyed and found to harbour an enhancer feature that augmented expression in conjunction with the promoter in cells of lung origin. The rs4446858 SNP present within the enhancer aligns with the binding motif of the IRF1 transcription factor, where the alternate C allele was found to respond to direct addition of IRF1 or its increase following IFN-γ stimulation, resulting in increased SLC6A14 expression. Our data support a conclusion that SLC6A14 expression in airway tissue is regulated, in part, by immune-responsive genetic features, likely involving goblet cells. While our findings support previous model system studies indicating beneficial acute effects of SLC6A14 expression, they also highlight a distinction between immune-related responses and cumulative effects of long term disease reflected as lung function in individuals with CF. Our studies emphasize the challenges of elucidating complex genetic loci where there are multiple levels of regulatory influence with competing contributions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00439-025-02800-7.

Tuberculosis (TB) treatment is highly effective, but response to therapy varies by geography and population subgroups. We assessed differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry according to major genetic ancestry groups (African, European, and Amerindian) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort using ADMIXTURE software. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. Outcomes attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Genetic ancestry proportions were evaluated as predictors in univariate and multivariable logistic regression models for each outcome, and in stratified models for each genetic ancestry group. There were 930 pulmonary TB patients included in this study. In multivariable models we observed a decreased risk of Grade 2 + ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20–0.85) and an increased risk for Grade 2 + ADR with increasing European genetic ancestry (OR 2.33, 95% CI 1.14–4.76). In secondary analyses evaluating the interaction of HIV and genetic ancestry, we observed a statistically significant interaction between HIV and African genetic ancestry, but significantly decreased risk for Grade 2 + ADR with increasing African ancestry proportion. There were no associations with Amerindian genetic ancestry or for other treatment outcomes. In this Brazilian TB cohort, increased toxicity risk was associated with decreased African and increased European ancestry proportion.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00439-025-02809-y.