Recessive variants in TWNK cause syndromes arising from mitochondrial DNA (mtDNA) depletion. Hearing loss is the most prevalent manifestation in individuals with these disorders. However, the clinical and pathophysiological features have not been fully elucidated. In this study, we collected five cases of hearing loss carrying bi-allelic TWNK variants from three unrelated Chinese families and identified two cases with isolated auditory neuropathy (AN) and three cases segregating with Perrault syndrome, characterized by AN, global developmental delay, and ovarian dysgenesis in females. All patients with cochlear implantation (CI) show poor speech discrimination outcomes, suggesting that the defect involves post-synaptic sites. In the mouse inner ear, Twinkle was immunolocalized to inner phalangeal cells and spiral ganglion neurons. Additionally, the broad expression pattern of Twinkle was observed in the auditory cortex, which to some extent explains the poor rehabilitation outcomes following CI. At the cellular level, Twinkle is localized at the mtDNA membrane, and the p.(Arg609AlaTer6) variant prevents the protein from reaching the mtDNA while the p.(Arg65Trp) variant exhibits a similar localization to the wild type, indicating a second mechanism of action. RT-PCR results indicated that the canonical transcript was abundant in the inner ear, while the shorter transcript was more abundant in the brain. Our findings revealed that bi-allelic TWNK variants lead to AN, which can be either syndromic or non-syndromic, with the molecular pathogenesis involving defects in mtDNA replication at post-synaptic sites. Patients with TWNK-associated conditions are not ideal candidates for CI and gene therapy may offer a solution for hearingrehabilitation.

Connexin 26, the protein encoded by the GJB2 (Gap junction protein beta 2) gene, is expressed in different tissues, including the cochlea and skin. Pathogenic DNA alterations in GJB2 cause autosomal recessive nonsyndromic hearing loss, whereas some GJB2 variants may lead to deafness-associated skin disorders. Genes encoding proteins of the Connexin26 molecular complex may fit as candidates to explain genetic hearing loss of yet unknown etiology. In search for Connexin26 direct protein partners, 120million clones of a human fetal brain cDNA library were screened for interaction with full-length Cx26 in a membrane yeast two-hybrid assay. Each Connexin26-interacting protein was submitted to a pipeline of in-silico characterization yielding a total of 40 direct interactors. It was disclosed that the mouse Gjb2 gene orthologue is coexpressed with 38 (95%) and 28 (70%) of the genes encoding Connexin26 interactors, respectively in specific cochlea cell types and embryonic keratinocytes. Interactors expressed in the organ of Corti supporting cells are significantly enriched in the gene ontology class of proteins with transporter activity (N = 10; 26%), seven of which are ion transporters. Nine interactor-encoding genes are either associated with deafness and/or skin disorders or have chromosomal mapping overlapping non-syndromic hearing loss-related loci. Altogether, the Connexin26 membrane interaction network highlights proteins with biological relevance to the physiology of cochlea and skin.

Despite advances in dermatogenomics, the global skincare industry continues to rely on generalized formulation strategies that overlook population-specific genetic variation. This study introduces a mutation-aware framework that bridges this translational gap through two novel metrics: the Mutation Burden Index (MBI)-which quantifies regional genetic vulnerability across nine core skin function domains-and the Population Compatibility Burden (PCB)-which measures the alignment between current commercial formulations and regional genomic needs. Using a curated database of more than 200 authenticated cosmeceutical products, we mapped ingredient functionality against regional MBI profiles. Results reveal a stark compatibility gap: regions with the highest burden (e.g., Africa, South Asia) receive the least functionally aligned products, with average compatibility scores as low as 0.35. In contrast, Europe-despite lower burden-achieves scores > 0.70. Simulated formulations informed by MBI scores increased compatibility to > 0.80 in underserved regions, demonstrating the potential for 50% gains in biological relevance without individualized genotyping. A machine learning classifier trained on MBI vectors achieved strong performance (F1 = 0.837), and SHAP-based interpretation highlighted barrier and pigmentation pathways as key drivers of product-region mismatch. In contrast to commercial AI platforms offer black-box personalization with minimal genomic input and no interpretability, our model provides transparent, biologically grounded, and reproducible formulation logic. By repositioning personalization from individual-level luxury to population-scale equity, this work establishes a practical foundation for genomically aligned skincare-anchored in functional biology, enabled by AI, and designed for global impact.

High-quality, regulatory-grade databases for precise genetic variant interpretation are critically needed for Chinese populations, where existing fragmented databases impede clinical effectiveness evaluations. We developed BRCA-CN, a consortium blockchain-based governance framework specifically designed for BRCA gene variant interpretation in Chinese populations. Our framework compiled 66,485 variants from 6,031 samples across six Chinese laboratories. A 15-expert panel conducted systematic variant curation using unified interpretation standards based on ACMG/AMP guidelines. Smart contracts ensured data integrity and accountability throughout the consensus process. After deduplication, we established a comprehensive database of 950 unique variants (BRCA1: 365, BRCA2: 585), completing consensus reviews for 607 sites with 462 achieving definitive interpretations. Comparison with ClinVar revealed 83.6% concordance, with AI validation (PrimateAI, REVEL, EVE) confirming high interpretation accuracy. The blockchain framework successfully enabled secure cross-institutional collaboration while maintaining data sovereignty and regulatory compliance. BRCA-CN demonstrates the transformative potential of blockchain technology in genomic medicine, addressing critical challenges in data sharing, standardization, and regulatory oversight. This framework provides a robust foundation for clinical decision-making and establishes a replicable model for population-specific genomic databases. Access to the BRCA-CN portal, user guides, and test data is provided in the supplementary materials, available at: https://oxygen-chamber.mgi-tech.com/sdb2.

The human leukocyte antigen (HLA) region is a critical genetic locus associated with diverse complex traits, yet its intricate genetic architecture poses significant challenges to elucidation. Leveraging recent advances in regional heritability estimation and extensive datasets from the Million Veteran Program (MVP), we conducted a comprehensive investigation of the HLA region's genetic architecture. This involved heritability estimation and genetic correlation analyses within the HLA region across European Americans (EAs) and African Americans (AAs). Our analyses demonstrated that in EAs, the HLA region exhibited significantly greater local heritability than other genomic regions of comparable length for lipid metabolic traits (triglycerides [TG], total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL]), anthropometric measures (body mass index [BMI]), and suicide-related traits (suicidal ideation without suicide attempts [IDE] and suicidal thoughts and behaviors [SITB]) (false discovery rate [FDR]-adjusted empirical p-values < 0.05). Notably, this enrichment was not observed in AAs. Genetic correlation analyses revealed disparities between local HLA and genome-wide findings. EAs exhibited 16 significant local HLA correlations and 32 genome-wide correlations. Conversely, AAs displayed more significant local genetic correlations within the HLA region (14 pairs) than genome-wide (3 pairs), with two pairs (IDE-SITB, LDL-TC) concordantly significant. These findings underscore the HLA region's substantial contribution to the variance of these lipid metabolic traits, BMI, and suicide-related traits. Further investigation into the genetic mechanisms by which HLA-mediated pathways influence these phenotypes is crucial for elucidating the complex role of this region, particularly concerning lipid metabolism and suicidal behaviors.

Genomics is revolutionizing medical science, offering transformative potential for the future of medicine. Advances in whole-genome sequencing have deepened our understanding of genome structure and function, paving the way for genomic medicine. The Human Genome Project has been instrumental in identifying genetic variations linked to increased disease risks, such as cancer, enabling genome-based diagnostics and personalized therapeutic strategies. Human genomics research focuses on developing precise therapies to enhance public health and address rare genetic disorders, including Spinal muscular atrophy, Duchenne muscular dystrophy, Parkinson's disease, and Huntington's disease. Cutting-edge gene-editing tools like CRISPR allow precise and targeted modifications with minimal side effects, improving treatment efficacy. By examining the interplay of genetic factors in health and disease, genomics lays the foundation for personalized medicine. This review highlights the impact of genomics on public health and its potential to reshape healthcare through innovative treatment strategies.

Discovering cancer driver genes is critical for improving survival rates. Current methods often overlook the varying functional impacts of mutations. It is necessary to develop a method integrating mutation pathogenicity and gene expression data, enhancing the identification of novel cancer drivers. To predict cancer drivers, we have developed a framework (DGAT-cancer) that integrates the pathogenicity of somatic mutation in tumors and germline variants in the healthy population, with topological networks of gene expression in tumors, and the gene expressions in tumor and paracancerous tissues. This integration overcomes the limitations of current methods that assume a uniform impact of all mutations by leveraging a comprehensive view of mutation function within its biological context. These features were filtered by an unsupervised approach, Laplacian selection, and combined by Hotelling and Box-Cox transformations to score genes. By using gene scores as weights, Gibbs sampling was performed to identify cancer drivers. DGAT-cancer was applied to seven types of cancer cohorts, and achieved the best area under the precision-recall curve (AUPRC ranging from 0.646 to 0.862) compared to five commonly used methods (AUPRC ranging from 0.357 to 0.629). DGAT-cancer has identified 505 cancer drivers. Knockdown of the top ranked gene, EEF1A1 indicated a ~ 41-50% decrease in glioma size and improved the temozolomide sensitivity of glioma cells. By combining heterogeneous genomics and transcriptomics data, DGAT-cancer has significantly improved our ability to detect novel cancer drivers, and is an innovative approach revealing cancer therapeutic targets, thereby advancing the development of more precise and effective cancer treatments.

Rare variants in prokineticin 2 pathway genes (PROK2; PROKR2), cause isolated hypogonadotropic hypogonadism (IHH) in humans, leading to pubertal failure and infertility. In addition to reproduction, this pathway is also implicated in cardiovascular, metabolic, and inflammatory regulation. The role of naturally occurring PROK2/R2 variants in the general population remains unknown. Thus, we aimed to investigate the role of PROK2/R2 variants in the overall human health. We performed a recall-by-genotype study in rare PROK2/R2 variant carriers and non-carrier controls from a large hospital dataset [Massachusetts General Brigham Biobank (MGBB)]. All recalled participants underwent medical history, physical exam, completed detailed questionnaires and laboratory evaluation including a frequently sampled intravenous glucose tolerance test. Continuous and categorical variables were analyzed with a t-test/non-parametric Wilcoxon rank sum test and a Fisher's exact test, respectively. Twenty-five rare PROKR2 variant carriers (11 males and 14 females, mean age 45.6 years ± SD 11.7) and 24 non-carrier controls (16 males and 8 females, mean age 44.8 years ± SD 10) were recruited. Male variant carriers were more likely to seek fertility evaluation compared to non-carrier controls (p = 0.03) and carriers of the founder PROKR2 (p.L173R) variant (44% of the cohort) in both sexes were more likely to be diagnosed with lower gastrointestinal phenotypes compared to controls (p = 0.02). This novel clinical association is in line with the reported role of prokineticin 2 in intestinal smooth muscle function in preclinical models. Rare heterozygous PROK2/R2 variants contribute to known reproductive and novel gastrointestinal phenotypes within a hospital-based population cohort.