Genetic variations contribute to the diversity of human traits and diseases, but their individual impact is small. polygenic risk scores (PRS) aggregate these effects across the genome to assess overall genetic risk. PRS aids in patient stratification, disease prediction, and personalized treatment, improving health outcomes. However, PRS transferability across populations is limited due to the predominantly European focus of genome-wide association studies (GWAS). Enhancing cross-population prediction accuracy is crucial for realizing PRS’s clinical potential and ensuring equitable access to effective therapies globally. Polygenic risk scores (PRS) aggregate the effects of numerous genetic variants to quantify inherited risk for complex traits and diseases. Although PRS have shown promise in risk stratification and precision medicine, their predictive performance often deteriorates when applied across populations, limiting clinical translation. While many LD-aware and multi-ancestry PRS methods have been proposed, it remains unclear how different PRS paradigms perform under realistic biobank-to-biobank transfer settings, particularly across traits with distinct genetic architectures. We utilize simulated and biobank data (Taiwan Biobank (TWB) and UK Biobank (UKB)) for height (1869 TWB individuals, 4,095,705 SNPs; 1056 UKB individuals, 339,550 SNPs) and Glaucoma (51,694 TWB individuals, 6,779,677 SNPs; 192,009 UKB individuals, 502,274 SNPs) to construct cross-population PRS models. We conducted both simulation studies and real-data analyses using the Taiwan Biobank (TWB) and the UK Biobank (UKB). Cross-population PRS models were constructed for height, a highly heritable quantitative trait, and glaucoma, a complex disease phenotype. We systematically compared population-structure-adjusted PRS (PRSadj) with LD-aware methods, including LDpred2 and Lassosum, as well as clumping and thresholding (C+T) as a baseline. Bi-directional prediction between biobanks was evaluated while adjusting for age and sex. PRS predictive performance and incremental value varied across traits, methods, and prediction directions. Under the primary C+T specification, adding PRS to the covariate model provided limited incremental predictive value for height, with ΔR2 ranging from −0.1844 to −0.0039 across the four within- and cross-population prediction settings. For glaucoma, the incremental contribution of C+T PRS was similarly modest, with ΔAUC ranging from −0.0200 to +0.0010. PC-adjusted sensitivity analyses showed that adjustment for population structure could alter the magnitude of predictive performance estimates, particularly for height. PRS performance and cross-population portability were context-dependent across traits, transfer directions, and modeling strategies. Incremental PRS value beyond baseline covariates was often modest, and no single method showed consistent superiority across all settings. These findings support multidimensional evaluation of PRS using incremental performance, portability, and calibration rather than absolute predictive performance alone.
Malformations of cortical development (MCD) are neurodevelopmental disorders arising from disrupted neuronal proliferation and migration during embryogenesis and represent a major cause of epilepsy and developmental impairment. Although numerous genes have been implicated, variant-specific mechanisms and population-specific mutational spectra remain incompletely defined, particularly in underrepresented regions. Here we investigated the genetic basis of MCD in three Tunisian families using whole-exome sequencing, segregation analysis, and high-resolution structural modelling. We identified a novel loss of function DENND5A mutation (p.Glu423LysfsTer13) in a patient with developmental and epileptic encephalopathy with severe global delay, cortical malformations and additional structural brain defects. We also report the first Tunisian case of a de novo DYNC1H1 linker-domain variant (p.Arg1623Gln) in a child with severe polymicrogyria, microcephaly and congenital cataracts, and show that this substitution disrupts conserved electrostatic interactions required for dynein linker stability. A de novo DCX mutation (p.Arg186Leu) was identified in a patient with lissencephaly-subcortical band heterotopia and support convergent destabilization of the doublecortin microtubule-binding interface across Arg186 substitutions, indicating residue-specific vulnerability in neuronal migration disorders. In addition, a truncating SEZ6L variant (p.Trp858Ter) a putative candidate autism linked gene, suggesting a potential modifying contribution to phenotypic variability. Collectively, our study expands the mutational spectrum of malformations of cortical development in North Africa and adds incremental evidence of the molecular underpinnings of MCD and contribute valuable data to genotype-phenotype correlations in neurodevelopmental disorders.
Updated safety warnings for base-modified messenger RNA (mmRNA) vaccines—such as increased risks of life-threatening myo(peri)carditis and the increased appearance of colorectal cancer in young adults—prompted our comprehensive review of this approach. Careful analysis of RNA biology textbook materials and the scientific literature identified serious conceptual, procedural, and translational issues that explain the shortcomings and potential public health risks of these injectables. The primary issues include using artificial pseudo-uridinated and methylated nucleosides based on the misleading information that these modified bases occur naturally and in sufficient numbers in eukaryotic mRNAs. In mmRNA vaccines, approximately 50
The transfer of nucleic acid from mitochondria to the nuclear genome produces nuclear–mitochondrial segments (NUMTs). Here, we identified a patient carrying a 34.8-kb duplication in DMD intron 1, with a 57.7-kb NUMT insertion located between these duplicated regions. Nanopore ultra-long sequencing revealed that this NUMT comprises eight concatenated mitochondrial fragments. Analysis of RNA validation revealed allele-specific expression of the DMD gene in the mother’s muscle tissue, highlighting the lack of transcription of the mutated DMD allele. To our knowledge, this case is the first documented instance of a genetic disorder resulting from the insertion of a concatenated NUMT.
Following the initial report linking immunoglobulin-binding protein 1 (IGBP1, OMIM 300139) mutations to X-linked intellectual disability (XLID), we identified a novel IGBP1 missense variant (c.145C>T, p.L49F) in an affected proband. The patient manifests with intellectual disability, global developmental delay, and corpus callosum hypoplasia, which are consistent with the phenotypes previously recorded in OMIM 300139. Functional assays reveal that IGBP1 L49F variant alters its binding with protein phosphatase 2A catalytic subunit alpha (PP2Ac) and calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα), disrupting CaMKIIα phosphorylation homeostasis. Our findings suggest that the IGBP1 L49F variant is a plausible genetic candidate for the XLID phenotype observed in this patient.
