Human Genetics最新文献

The multiplexed layers of regulatory processes and mechanisms within a cell are, to a degree, encoded in our genome. Unravelling the relationship between DNA sequence and molecular processes is crucial for understanding evolution, interpreting and predicting the consequences of genomic variation. Furthermore, understanding the extent to which DNA sequence contributes to the genome organisation can help reveal the aspects more influenced by other factors. Therefore, here we provide a succinct summary of the emerging genomic sequence code or "grammar" of genomic contact formation and 3D genome organisation. Drawing on different types of evidence from multiple disciplines, from large-scale genomic studies, biochemical in vitro assays, and computational analyses utilising machine learning and other modelling techniques, we aim to inform future research on the present associations between 3D genome organisation and sequence.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) levels, leading to early-onset cardiovascular disease. FH is primarily caused by pathogenic variants in the LDLR gene, affecting cholesterol metabolism. We describe a family with a mild form of FH, in which gene panel sequencing identified a novel c.-8C>A variant in the LDLR 5'UTR. To assess its functional impact, we performed a luciferase assay and found that this variant partially reduces LDLR protein translation efficiency by introducing a novel upstream AUG (uAUG) start codon. This partial reduction in LDLR activity is consistent with the mild phenotype observed in the family. Additionally, we analyzed three previously reported LDLR 5'UTR variants (c.-5C>T, c.-14C>A, and c.-23A>C) but did not observe any significant effect on LDLR expression, suggesting that these variants are unlikely to contribute to disease development. These findings highlight the role of 5'UTR variants in LDLR expression and emphasize the importance of functional studies in variant classification for FH diagnostics.

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.

Genome Language Models (GLMs) represent a transformative convergence of artificial intelligence (AI) and genomics, offering unprecedented capabilities for biological discovery, healthcare innovation, and therapeutic design applications. However, these powerful tools create novel regulatory challenges that existing frameworks-whether AI governance or genomic privacy protections-cannot adequately address alone. This paper examines the critical regulatory gaps emerging at this intersection, highlighting tensions between AI principles that favor broad data access and genomic governance that demands stringent privacy protections and informed consent. We analyze how GLMs challenge conventional regulatory approaches as they pertain to applications in disease risk prediction, international research collaboration, and open-source model distribution. We propose a multilayered governance framework that combines policy innovations such as regulatory sandboxes and certification frameworks with technical solutions for privacy preservation and model interpretability. By developing adaptive governance strategies that bridge AI and genomic regulation, we can enable responsible GLM innovation while safeguarding individual rights, promoting equity, and addressing emerging biosecurity concerns in this rapidly evolving field.

Although variants in DNAH family genes have been suggested as a main contributor to asthenozoospermia in humans, the role of DNAH7 on male fertility remains largely unexplored. In this study, loss-of-function variants in DNAH7 were identified in two unrelated infertile men with asthenozoospermia through whole exome sequencing, including compound heterozygous variants c.9702_9705del (p.Phe3234Leufs*52) and c.768G > A (p.Trp256*) in Patient 1, and compound heterozygous variants c.5650 C > T (p.Arg1884*) and c.768G > A (p. Trp 256*) in Patient 2. Interestingly, transmission electron microscopy results indicated a severe loss of inner dynein arms (IDAs) in the sperm flagella of both patients. Furthermore, immunofluorescent staining revealed a marked reduction of DNAH7 and other IDA-associated proteins, such as DNAH3 and DNAH6, in the patients' spermatozoa. In contrast, the expression of the outer dynein arms (ODA)-associated proteins, including DNAH8, DNAH11, DNAH17 and DNAI1, was comparable to that in normal controls. Moreover, the infertility of the patients harboring DNAH7 mutations could be successfully overcome by intracytoplasmic sperm injection treatment. Taken together, our findings confirmed that DNAH7 variants may contribute to asthenozoospermia by affecting flagellar IDA assembly, thereby enhancing our understanding of phenotype-genotype correlations in male infertility.

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.

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.

FBRSL1-associated syndrome is a rare congenital malformation and intellectual disability syndrome caused by heterozygous truncating variants in Fibrosin-Like 1 (FBRSL1). While FBRSL1 is known to be involved in embryonic development, its precise molecular function remains poorly understood. Therefore, the aim of this study was to elucidate the molecular function of FBRSL1, which is thought to be essential for developmental processes, and to investigate the effect of patient-derived truncating FBRSL1 variants. Using chromatin immunoprecipitation followed by sequencing (ChIP-Seq), we show that FBRSL1 regulates the expression of epigenetic regulators. We demonstrate that FBRSL1 associates with the transcription factor Yin Yang 1 (YY1) and binds upstream of Bromodomain And PHD Finger containing 1 (BRPF1) and Lysine Acetyltransferase 6 A (KAT6A), two epigenetic regulators involved in embryonic development and linked to neurodevelopmental disorders. Furthermore, quantitative real-time PCR analysis revealed that truncating FBRSL1 variants lead to downregulation of BRPF1 and KAT6A in blood and fibroblasts derived from patients with the FBRSL1-associated syndrome. Consistently, loss of Fbrsl1 function in Xenopus laevis embryos, which results in a range of developmental abnormalities, including craniofacial and brain malformations, also leads to defects in the brpf1 and kat6a expression pattern. In summary, our findings support a function of FBRSL1 in regulating key genes involved in global epigenetic processes and embryonic development. These results provide mechanistic insights how FBRSL1 dysfunction contributes to the pathogenesis of FBRSL1-associated syndrome.