Early-onset myopia exhibits substantial genetic heterogeneity, with variants in ARR3 increasingly recognized as an important X-linked cause. In this study, we investigated the genotypic spectrum and associated clinical phenotypes of ARR3 variants in seven families with early-onset myopia, including one male with somatic mosaicism. Comprehensive ophthalmic examinations were performed in probands and available relatives. Genetic analysis was conducted using whole-exome sequencing with Sanger confirmation, and buccal-tissue sequencing was additionally performed in the mosaic case. In total, five novel variants and one previously reported variant in ARR3 were identified. Longitudinal analysis of 110 spherical equivalent refraction measurements and 112 axial length measurements over a mean follow-up of 4.6 years (range, 0.5–11 years) showed a faster axial elongation in males compared with females (0.48 mm/year vs. 0.26 mm/year, P = 0.0006), while refractive progression rates were not significantly different (−0.60 D/year vs. −0.33 D/year, P = 0.617). Electroretinography revealed reduced photopic and scotopic responses. The mosaic male (c.39 G > C, p.Lys13Asn) showed moderate myopia at baseline and progressive axial elongation. These findings expand the variant spectrum of ARR3 and highlight phenotypic variability between males and heterozygous females, while the identification of a mosaic case provides additional insight into the potential modifying role of somatic mosaicism in disease expression.
CASK-related disorders comprise two main phenotypes: severe microcephaly with pontocerebellar hypoplasia (MICPCH), typically caused by truncating variants, and milder X-linked intellectual disability (XLID), usually associated with missense variants. We aimed to characterize this molecular spectrum within an underrepresented national cohort. We evaluated 18 affected individuals from 16 unrelated families with CASK variants identified through exome or genome sequencing. Clinical, neurodevelopmental and neuroimaging findings were systematically reviewed. Selected missense variants were evaluated by in silico prediction tools and structural modeling. We identified 16 distinct CASK variants, 11 of which are novel, including frameshift, stop-gain, splice-site, and missense variants, as well as one large deletion. Consistent with known genotype-phenotype correlations, null alleles resulted in the severe MICPCH phenotype, while presumed hypomorphic alleles were associated with XLID. However, unlike previous reports, our MICPCH patients exhibited a higher frequency of dysmorphic facial features (86%), skeletal anomalies (57%) and sensorineural hearing loss (43%). Furthermore, contrary to the literature suggesting a milder epilepsy in females due to X-inactivation, 63% of our female patients with MICPCH presented with recurrent seizures. This cohort broadens both the molecular and phenotypic spectrum of CASK-related disorders. Findings reinforce that truncating variants predominantly cause MICPCH, while missense variants can lead to various outcomes depending on domain-level structural impact. We demonstrate that the CASK phenotypic spectrum is broader than previously recognized, frequently involving distinctive facial dysmorphism, skeletal defects and hearing impairment, suggesting that CASK plays a critical role not only in synaptic function but also in wider developmental processes.
Recent advances in hereditary dementia research have clarified its molecular pathogenesis and clinical applications, with several advances already reaching implementation. The late 2023 introduction of anti-amyloid β therapies for Alzheimer's disease (AD) in Japan marked the beginning of a transformative era, though amyloid-related imaging abnormalities (ARIA) remain a notable adverse effect. Because APOE genotype, and ε4 dose in particular, is a major determinant of ARIA, genotyping is now embedded in pretreatment assessment. This review examines how one national health system has incorporated these advances and distinguishes between two frequently conflated domains: real-world clinical practice and clinical research. Practically, we describe the Guidelines for the Appropriate Use of APOE Genetic Testing in Dementia, established in 2025 and revised in 2026 following national health insurance approval, which position APOE testing as a pharmacogenetic tool governing monitoring intensity rather than treatment eligibility. We consider what the lower ε4 allele frequency in Japan implies, now that per-genotype effect estimates have been revised to values comparable to those in European-ancestry populations, and we set out the counseling required when a pharmacogenetic result carries risk information for untested relatives. On the research side, we describe the Hereditary Dementia Trial Ready Cohort, a national registry spanning 21 causative genes, and explain why its scope diverges from that of autosomal dominant AD-focused international initiatives such as DIAN. We conclude that features of the Japanese experience are most likely to be transferred to other healthcare systems.
Focal cortical dysplasia (FCD) is a malformation of cortical brain development, yet its genetic basis remains incompletely understood. Here, we investigate type II FCD in a proband with behavioral disturbances, including aggression, hyperactivity, and sleep dysfunction, but with normal early development and cognition. Magnetic resonance imaging (MRI) of the proband revealed focal cortical thickening, abnormal sulcation, and gray-white matter blurring in the left temporal lobe, consistent with FCD type II. Whole-exome sequencing identified a novel homozygous missense variant in C2ORF78 (c.1264 A > G; p.Ser422Gly), absent in population databases. The S422 residue is evolutionarily conserved, resides within a disordered, solvent-accessible region, and its substitution with glycine caused marked structural destabilization, cytosolic mislocalization, and protein aggregation. Functional studies in proband fibroblasts revealed no significant reduction of C2ORF78 protein, deregulated mTOR signaling, impaired autophagy, ER stress, and G0/G1 cell cycle arrest. Molecular dynamics simulations confirmed significant loss of protein stability and compactness in the S422G mutant. C2ORF78 interacts with RNA-binding and transcriptional regulators, and gene ontology analyses indicated roles in transcription and RNA splicing. We propose that C2ORF78 functions as a transcriptional coregulator of genes negatively regulating mTOR signaling. Mislocalization of the S422G mutant leads to a loss of nuclear function, resulting in hyperactivation of mTOR and disrupted cellular homeostasis. High expression of C2ORF78 in cerebral cortex and hippocampus supports its relevance to brain physiology. Our findings identify C2ORF78 as a novel candidate gene associated with FCD type II and highlight transcriptional dysregulation of mTOR signaling as a potential pathogenic mechanism.
Uniparental diversity in the Sanjiangyuan region, the pastoralist interior of the Qinghai–Tibet Plateau, is uncharacterised. We analysed Y-chromosomal haplogroups in 547 males and mitochondrial haplogroups in 623 samples from a cohort of 1 226 Tibetans in Qumalai and Tanggula, with household pedigrees for 470 Tanggula participants. Both fall within Tibetan variation yet are separable on both marker systems. Qumalai carries haplogroup D at 74.3% (effective haplogroup number 1.74), matched among the Tibetan reference samples only by Nagqu; Tanggula lies within the published range at 2.48. Two features mark the Tanggula maternal pool. The West Eurasian lineage U7, on 26 carriers, stands at 5.6% of assigned samples (26/467; 95% CI 3.5–7.7%), 10.3% of the quality-filtered set (26/252), at or above the highest value recorded on the plateau (5.3%) under every treatment, although the most conservative interval includes it; the carriers fall in 12 matrilines occupying half the households expected by chance (P < 0.0001). Haplogroup Z, present in Qumalai in every Tibetan reference sample, was not observed in Tanggula (P = 7 × 10⁻⁴ among informative assignments). Paternal haplogroup diversity differs significantly between the communities, while maternal diversity does not, at both levels and on an unbounded scale. Raw FST is not comparable across these marker systems: its attainable maximum ranges from 0.343 to 0.024 across four levels; standardised measures reverse the ordering. Sanjiangyuan Tibetans are not a genetically homogeneous unit; the large valley Amdo samples on which the published picture chiefly rests do not span plateau paternal diversity.
