Thalassemia, a genetically inherited hemoglobinopathy, represents a significant global health challenge with profound socioeconomic implications, particularly in endemic regions. The emergence of third-generation sequencing (TGS) technologies has revolutionized thalassemia research and diagnostic paradigms, offering unprecedented capabilities for comprehensive genetic characterization. Between 2021 and 2024, we conducted a comprehensive analysis of 536 clinically suspected thalassemia cases from southern China, conventional diagnostic methods and Nanopore TGS were performed simultaneously. Among the 536 subjects analyzed, TGS identified 332 cases harboring either common or rare variants, which included 160 cases with rare thalassemia variants, 50 cases with abnormal hemoglobin variants, and 122 cases carrying common α- or β-thalassemia mutations. --THAI and HKαα emerging as the most prevalent variants among rare thalassemia, followed by Chinese (Aγδβ)0 and α-Fusion gene. The predominant abnormal hemoglobin was Hb New York (HBB:c.341 T > A). We used TGS and discovered three rare variants that have not been identified by conventional diagnostic methods for thalassemia, the variants included two cases of α-globin chain 32.8 kb deletions and one case of β-globin chain 3.5 kb deletion. Hb G-Ferrara (HBB:c.174 C > A) and Hb Ethiopia (HBA2:c.421 T > C) were firstly identified in the Chinese population. Moreover, two novel α-globin variants: NC_000016.10:g.176260-176930del and HBA1:c.386 T > C were discovered in this study. This study expands the genetic landscape of hemoglobinopathies in Southern China by characterizing a comprehensive spectrum of rare variants. Our findings demonstrate the superior diagnostic capability of TGS in identifying rare thalassemia genotypes, suggesting its potential as a first-line molecular diagnostic tool for comprehensive hemoglobinopathy screening.

Several polygenic risk scores (PRSs) for type 2 diabetes (T2D) have been derived from genome-wide association studies (GWASs), but Pacific populations have generally not been represented in these GWASs. The aim of this study was to examine the association of PRS for T2D with diabetes and clinical measures in Pacific Islander populations from Guam and Saipan. We analyzed seven constructions of PRSs in 1990 participants in a GWAS from a community-based cross-sectional study of diabetes. Associations of T2D PRS with diabetes, maximum body mass index (BMI), fasting glucose, and HbA1c were examined with adjustment for age, sex, and the first four genetic principal components (PCs) from the GWAS (to account for population stratification). Insulin resistance/secretion measures were also analyzed in 989 participants without diabetes. All seven PRSs were strongly associated with T2D (p < 5 × 10-9 for each); a 1-SD increase in the PRS was associated with 39-81% increase in the odds of T2D (i.e., standardized odds ratio [OR] ranging 1.39-1.81) adjusting for age, sex, and PCs. We also found that a 1-SD increase in the PRS was associated with 0.30-0.46 mmol/L higher fasting glucose, and with 2.68-4.63 mmol/mol higher HbA1c adjusting for age, sex, and PCs. We found no associations of PRSs with maximum BMI or insulin measures. All seven of the T2D polygenic risk scores evaluated associated significantly and strongly with diabetes, fasting glucose and HbA1c. These analyses suggest that T2D polygenic scores, as currently derived, have a certain degree of transferability to individuals from Pacific populations.

Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant inherited neurodegenerative disease caused by NOTCH2NLC GGC repeat expansions. A high-intensity signal in the corticomedullary junction (CMJ) on magnetic resonance (MR) diffusion-weighted imaging (DWI) is a well-known characteristic of NIID. However, because of its diverse clinical symptoms and frequent presence of cerebral white matter hyperintensity (WMH) lesions on MRI, patients with NIID may be suspected of having other leukoencephalopathies. The aim of the present study was to identify patients with NOTCH2NLC GGC repeat expansions among those with undiagnosed leukoencephalopathies, recruited from NOTCH3-negative cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-suspected and GFAP-negative Alexander disease (AxD)-suspected patients. Among 459 NOTCH3-negative CADASIL-suspected patients, 18 (3.9%) showed NOTCH2NLC GGC repeat expansions; however, among 40 GFAP-negative AxD-suspected patients, none exhibited such repeat expansions. On comparing 17 patients with GGC repeat expansions, whose clinical information was available, with 179 CADASIL probands previously reported by us, the former showed significantly higher frequencies of seizure (23.5 vs. 6.9%, respectively), WMH in the corpus callosum (92.9 vs. 9.2%, respectively), paravermis (21.4 vs. 2.7%, respectively), and middle cerebellar peduncle (21.4 vs. 3.4%, respectively), and DWI high-intensity signals in CMJ (61.5 vs. 1.4%, respectively). In conclusion, not only DWI high-intensity signals in CMJ, but also the WMH distribution, particularly a high frequency in the corpus callosum, and presence of seizures are useful for detecting NIID in patients with undiagnosed leukoencephalopathies.

Grange syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in the YY1AP1 gene. It is clinically characterized by multisystem involvement, including vascular stenosis, brachysyndactyly, osteopenia, cardiac anomalies, and neurodevelopmental delay. Our case was followed up in the Child and Adolescent Psychiatry clinic with the diagnosis of intellectual disability. Whole-exome sequencing (WES) was performed, and Sanger sequencing was used to confirm the identified variant and conduct familial segregation analysis. We report a 17-year-old Turkish female who presented with academic failure, speech delay, dysarthria, facial dysmorphism, and surgically corrected hand syndactyly. Notably, she exhibited no clinical signs of vascular stenosis or hypertension at the time of diagnosis. A novel compound heterozygous variant combination in YY1AP1 (NM_139119.3) was identified: c.1489_1492del (p.Glu636ProfsTer13), previously reported as pathogenic, and c.1637_1638del (p.Pro546ArgfsTer26), a novel frameshift variant. These variants were maternally and paternally inherited, respectively. This is the first reported case of Grange syndrome diagnosed based on neurodevelopmental and dysmorphic findings before the onset of vascular or hypertensive symptoms. Our findings highlight the importance of considering YY1AP1-related pathology in the differential diagnosis of intellectual disability and syndactyly, even in the absence of vascular features. Early genetic diagnosis enables clinical surveillance for life-threatening complications associated with this syndrome.

This study aims to evaluate the impact of four SNPs of human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene, and its interaction with smoking and alcohol drinking on the risk of nasopharyngeal carcinoma (NPC). Hardy-Weinberg equilibrium (HWE) and the relationship between four SNPs of the hOGG1 gene and the risk of NPC were tested using the SNPStats online software ( https://www.snpstats.net/start.htm ). Generalized multifactor dimensionality reduction (GMDR) was utilized to screen the optimal interaction combinations among four hOGG1 gene SNPs, smoking, and alcohol drinking. We found that rs1052133- Cys allele was associated with increased NPC risk, ORs (95% CI) were 1.42 (1.12-1.85) for Ser/Cys genotype, 1.95 (1.51-2.48) for Cys/Cys genotype, 1.57 (1.18-2.05) for Ser/Cys or Cys/Cys genotype, compared to Ser/Ser genotype. We also found that rs159153- T allele was associated with increased NPC risk, ORs (95% CI) were 1.35 (1.06-1.73) for CT genotype, 2.18 (1.62-2.85) for TT genotype, 1.45 (1.09-1.90) for CT or TT genotype, compared to CC genotype. However, we did not find any statistically significant impact of the minor alleles of rs3219008 and rs293795 on the risk of NPC. GMDR model found a significant gene-environment interaction combination (two-locus model with P = 0.018) between rs1052133 and smoking. Compared to never smokers with rs1052133 Ser/Ser genotype, ever or currently smokers with rs1052133- Ser/Cys or Cys/Cys genotype have the highest NPC risk, OR (95% CI) = 3.18 (1.94-4.42). The rs1052133 and rs159153 minor alleles, the interaction between rs1052133 and smoking, were all associated with increased NPC risk.

Wilson's disease (WD) is a rare genetic disorder of copper transport due to mutations in the ATP7B gene. This results in copper overload and tissue damage that is most evident in the liver and brain. Over 1000 pathogenic mutations have been found in WD patients, and of these, mutations within the ATP7B coding region predominate. In this study, we perform functional analyses of 7 rare sequence variations in the promoter region of the ATP7B gene. We performed dual luciferase reporter assays in HepG2 and SH-SY5Y cell lines under basal conditions and after the addition of 10 μM or 40 μM concentrations of CuSO4. The results showed that promoter activity varied both according to the haplotype and the cell line used. Our results suggest a potential role of promoter polymorphisms in the variation of ATP7B gene expression with probable implications in copper accumulation in the organism and consequent phenotype variation in WD. In addition, given the association of copper concentration and ATP7B expression in the brain, promoter polymorphisms could act as susceptibility determinants of neurodegeneration in the most common late-onset nervous system diseases. Finally, promoter involvement in ATP7B overexpression and platinum resistance presents new mechanisms of great importance that need to be better understood. Further experimental and clinical studies are necessary to further explore the role of the ATP7B promoter in copper and platinum management. These studies will offer new insights for the development of molecular therapies for brain degenerative and tumor diseases.

Prenatal genetic testing in Japan has undergone major changes over the past 2 decades. Maternal serum screening (MSS), amniocentesis (AC), and chorionic villus sampling (CVS) have been the principal tools used to identify fetal chromosomal abnormalities. Recently, non-invasive prenatal testing (NIPT) has reshaped clinical decision-making. However, updated national-level data capturing trends in conventional prenatal testing methods are limited. We aimed to assess the current landscape of prenatal genetic testing in Japan. To update the national data, we compiled test volumes from five major high-volume laboratories that analysed prenatal genetic tests and conducted a supplemental nationwide questionnaire-based survey on ultrasound (US)-only screening between 2020 and 2023. Over this period, MSS declined from 34,887 cases in 2018 to 25,553 in 2023, AC from 16,454 in 2014 to 5620 in 2023, and CVS from 2149 in 2015 to 1167 in 2023, whereas US-only screening increased slightly to >10,000 cases annually. The chromosomal abnormality detection rate among AC cases increased from 8% during 2006-2014 to 20.0% in 2023, with trisomy 21 comprising 43.6% of the cases. During the same period, the proportion of mothers aged ≥35 years increased from 14.0% in 2003 to 30.4% in 2023, whereas the proportion of national live births decreased by 35.3%. Thus, declining test volumes cannot be attributed solely to demographic changes but also reflect the influence of NIPT uptake, improved pretest risk stratification, and changing reproductive decision-making supported by expanding genetic counselling. This study provides foundational data for future prenatal genetic testing practices and policies in Japan.

Sarcoidosis is a heterogenous inflammatory disease with complex genetic susceptibilities. Multi-ethnic genome-wide association studies have validated the association of sarcoidosis susceptibilities with single nucleotide variants on interleukin 23 receptor gene (IL23R), which is highly expressed in adrenal gland and testis, but not in skeletal muscle. Here we report concomitant ectopic expression of a canonical IL23R transcript and alternative polyadenylation of intron 6 of IL23R, leading to novel aberrant transcripts containing two retrotransposons, LINE1 (L1PA16) and THE1A, in the 3' untranslated region (IL23RL1-THE1A), in sarcoid myopathy (SM) compared with non-SM disease controls. RT-qPCR confirmed the expression of both transcripts in an additional sample set, including 14 SM and 29 non-SM. We also observed expression of both transcripts in T cells by single-nucleus RNA-sequencing. These findings should serve as an additional resource for investigating the role of IL23R transcript variants in the genetic background of sarcoidosis susceptibility and other inflammatory diseases.

Argyrophilic grain (AG) is a common neurodegenerative accumulation of 4 repeat tau in dendritic spine. Dementia with grain (DG) is defined as AGs with a sole pathological basis for cognitive decline. As with other multifactorial diseases, DG could result from interactions of environmental and genetic factors. However, the genetic basis of DG is largely unknown. To clarify the genetic architecture of DG pathogenesis, we conducted a genome-wide association study (GWAS) with 214 DG cases versus 12,405 controls. We have identified a candidate locus associated with the risk of DG, the SVIL locus on chromosome 10, with genome-wide significance (rs11595141, P = 4.86 10-8) in the GWAS. Transcriptome-wide association analysis using summary statistics for DG-GWAS identified DAPK2 (PTWAS = 3.68 10-5) as a novel candidate causal gene for DG pathogenesis in the brain frontal cortex. The genetic association analysis for the APOE locus revealed that the APOE allele did not affect DG pathogenesis. We also identified new variants in the MAPT encoding tau protein that could potentially affect DG pathology. This is the first GWAS for DG, and our genetic findings provide biological and clinical insights into the pathogenesis of DG.