NPJ Genomic Medicine最新文献

Polygenic risk scores (PRSs) are promising tools for genetic risk stratification, but their performance across ancestries remains uncertain. We evaluated 64 published PRSs for eight cardiometabolic traits in 4879 Thai individuals using imputed SNP-array data. Cross-sectional and six-year longitudinal analyses were performed to assess predictive performances. PRSs for type 2 diabetes (T2D) and lipid traits showed the strongest utility, with the best-performing LDL-C and TC scores explaining up to 9.8% and 7.8% of trait variance, respectively. The T2D PRS achieved an area under the curve (AUC) of 0.70 and consistently stratified disease risk over time. In contrast, PRSs for glycemic traits and cardiovascular disease (CVD) had weaker predictive value; notably, the best-performing CVD PRS showed an inverse association with disease risk. Reduced SNP retention and ancestry-related linkage disequilibrium differences contributed to variability. These findings highlight both the potential and current limitations of PRSs in underrepresented Southeast Asian populations.

Impairment of axonal transport has been emphasized as a common feature in a series of neurodegenerative diseases (NDs). Variations in DCTN1 have been reported in NDs such as Parkinson's disease (PD), Perry syndrome (PS) and Amyotrophic lateral sclerosis (ALS). The overall objective of this study was to investigate the contribution of DCTN1 variants in different NDs and to explore the correlation between DCTN1 variants and disease phenotypes. We identified a previously published mutation p.G71E in three unrelated PS families. In the PD cohort, 30 putative deleterious variants (PDVs) were identified in DCTN1. Gene-based burden analysis showed a nominal association between DCTN1 rare PDVs and PD (uncorrected p = 0.042); however, this association did not remain statistically significant after multiple testing correction (FDR-corrected p = 0.084). In the ALS cohort, 10 PDVs were all rare damaging missense variants, and the PDVs were not enriched in ALS patients. Our findings first provide the independent evidence that PDVs in DCTN1 may be a risk factor for PD, but do not support the genetic involvement of DCTN1 in ALS of Asian ancestry.

Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3'-UTR SNP rs78378222-T's association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28-1.62, P = 1.76 × 10^-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37-1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date - demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

While Research Electronic Data Capture (REDCap) is widely adopted in rare disease research, its unconstrained data format often lacks native interoperability with global health standards, limiting secondary use. We developed RareLink, an open-source framework implementing our published ontology-based rare disease common data model. It enables standardised data exchange between REDCap, international registries, and downstream analysis tools by linking Global Alliance for Genomics and Health Phenopackets and Health Level 7 Fast Healthcare Interoperability Resources (FHIR) instances conforming to International Patient Summary and Genomics Reporting profiles. RareLink was developed in three phases across Germany, Canada, South Africa, and Japan for registry and data analysis purposes. We defined a simulated Kabuki syndrome cohort and demonstrated data export to Phenopackets and FHIR. RareLink can enhance the clinical utility of REDCap through its global applicability, supporting equitable rare disease research. Broader adoption and coordination with international entities are thus essential to realise its full potential.

Muscle phosphorylase kinase deficiency results from X-linked pathogenic variants in PHKA1, leading to glycogen storage disease (GSD) type IXα1 (also known as GSD IXd). As part of an international collaboration, we describe 14 previously unreported cases (12 males, 2 females; ClinicalTrials.gov NCT04454216, registered 2020-07-01). We compared our cohort to 18 cases previously reported and to an additional 16 cases identified through the National Institutes of Health All of Us Research Program. The clinical presentations highlight the predominance of myopathic symptoms on exertion and emphasize the variability in age of onset. Examination of muscle biopsies revealed glycogen accumulation and an increase in lipid droplets indicative of mitochondrial dysfunction and mitophagy. We encourage clinicians to maintain a high level of suspicion even in the setting of normal blood creatine kinase levels. Comprehensive longitudinal natural history studies remain necessary to improve disease detection, inform management guidelines, and provide a foundation for therapeutic development.

The germline genetic susceptibility to adult glioblastoma remains unclear. With the option of broad molecular testing, it is crucial that clinicians are aware of the a priori probability of finding germline predisposition in glioblastoma patients. Here, we studied the genetic predisposition to adult glioblastoma using paired tumor-normal WGS data in an unselected, average cohort of 92 glioma WHO grade 4 patients. In 10 patients (11%), 12 Pathogenic Germline Variants (PGVs) were found in genes strongly associated with familial glioblastoma (MSH6 (3x), PMS2 (5x), MSH2, NF1, BRCA1) or medulloblastoma (SUFU). In six of these patients (60%), causality was supported by a second (somatic) event and/or a matching genome-wide mutational signature. Thus, germline predisposition does play a role in the development of adult glioblastoma, with mismatch repair deficiency being the main mechanism. Our results also highlight the benefits of tumor-normal WGS for glioblastoma patients and their families, beyond identifying actionable mutations for therapy.

This study aimed to evaluate the feasibility of whole-genome sequencing (WGS) combined with computational tools for spinal muscular atrophy (SMA) carrier screening and disease diagnosis in Taiwan. WGS data from 1492 Taiwan Biobank participants and two patients with SMA were analysed to determine the SMN1 and SMN2 copy numbers using Illumina DRAGEN SMN Caller and validated by multiplex ligation-dependent probe amplification (MLPA). Among 1480 samples analysed, 23 SMA carriers were identified, yielding a carrier frequency of 1.55%. MLPA confirmed the accuracy of SMN1 and SMN2 copy number results detected using WGS. Both patients with SMA presented compound heterozygous variants with one SMN1 copy loss and the other SMN1 variant, specifically SMN1,c.815A>G, and SMN1,c.81+2_81+3delTG, respectively. Taken together, combining WGS with advanced bioinformatics tools is a feasible and promising approach for SMA carrier screening and disease diagnosis.

Missense and loss-of-function variants in SPECC1L are associated with Teebi Hypertelorism Syndrome 1 (TBHS1). Here, we report a novel SPECC1L intragenic deletion encompassing exon 3, which contains the canonical translation start site, in two related individuals with craniofacial features consistent with TBHS1. We use functional overexpression assays to demonstrate that this deletion leads to alternative start codon usage and protein truncation. This is the first report of a SPECC1L intragenic deletion associated with TBHS1. Our findings suggest that deletion of the canonical N-terminal disordered region of SPECC1L contributes to craniofacial anomalies, warranting further investigation into its role in neural crest development.

Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: CEP83 NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of CEP83 5'UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. CEP83 biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function CEP83 variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.

Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder. This study used whole-genome sequencing (WGS) to investigate the genetic basis of AIS in 119 patients from 103 families. Our WGS analysis identified known pathogenic or protein-truncating variants in 15 probands, and other strong or moderate candidate variants in 69 additional patients. We found both coding and non-coding mutations, including structural variants. Candidate genes included known AIS genes (e.g., COL11A2, FBN1) and genes linked to other musculoskeletal disorders with scoliosis (e.g., RYR1). Association analysis confirmed four known AIS single-nucleotide polymorphisms in our cohort. Gene set enrichment analysis revealed four gene clusters related to skeletal muscle contraction, extracellular matrix, and gene expression regulation. This WGS-based approach identified clinically relevant genetic variations and biological pathways in AIS patients, offering valuable insights into its complex development.