UBR4 should no longer be considered a candidate gene for episodic ataxia type 8
Related Articles
Another common genetic ataxia in South Korea: Spinocerebellar ataxia 36
Spinocerebellar ataxias (SCAs) represent a diverse group of neurodegenerative disorders characterized by progressive cerebellar ataxia. In South Korea, diagnostic laboratories typically focus on common SCA subtypes, leaving the prevalence of rare SCAs uncertain. This study aimed to explore the frequency of rarer forms of SCA, including SCA10, 12, 31, and 36 utilizing molecular techniques including long-read sequencing (LRS). Patients from ataxia cohorts who remained undiagnosed after testing for common genetic ataxias (SCA1, 2, 3, 6, 7, 8 17, and dentatorubral-pallidoluysian atrophy) were analyzed, along with unselected ataxia patients referred for screening of common SCAs. Expanded alleles for SCA10, 12, 31, and 36 were investigated through allele-length PCR, repeat-primed PCR, and LRS. Among 78 patients from 67 families with undiagnosed cerebellar ataxia, SCA36 was identified in 8 families (11.9%), while SCA10, 12, or 31 were not found. In unselected ataxia, SCA36 was present in 1.0% (1/99). Korean SCA36 patients exhibited clinical characteristics similar to global reports, with a higher incidence of hyperreflexia. The haplotype of expanded alleles identified in LRS was consistent among SCA36 patients. The findings indicate that SCA36 accounts for 11.9% of diagnoses after excluding common SCAs and 1.0% in unselected ataxia patients. The study underscores the prevalence of SCA36 in South Korea and emphasizes the potential of LRS as a diagnostic tool for this condition. Integrating LRS into diagnostic protocol could enhance diagnostic efficacy, particularly in populations with a high prevalence of SCA36 like South Korea. Further research is necessary to standardize LRS for routine clinical application.
Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining
Identification of novel drug targets is a key component of modern drug discovery. While antimalarial targets are often identified through the mechanism of action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space is also constrained by existing compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed the Plasmodium falciparum genome and identified 867 candidate protein targets with evidence of small-molecule binding and blood-stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 27 high-priority antimalarial target candidates. This study also provides a genome-wide data resource for P. falciparum and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.
Neural codes track prior events in a narrative and predict subsequent memory for details
Throughout our lives, we learn schemas that specify what types of events to expect in particular contexts and the temporal order in which these events usually occur. Here, our first goal was to investigate how such context-dependent temporal structures are represented in the brain during processing of temporally extended events. To accomplish this, we ran a 2-day fMRI study (N = 40) in which we exposed participants to many unique animated videos of weddings composed of sequences of rituals; each sequence originated from one of two fictional cultures (North and South), where rituals were shared across cultures, but the transition structure between these rituals differed across cultures. The results, obtained using representational similarity analysis, revealed that context-dependent temporal structure is represented in multiple ways in parallel, including distinct neural representations for the culture, for particular sequences, and for past and current events within the sequence. Our second goal was to test the hypothesis that neural schema representations scaffold memory for specific details. In keeping with this hypothesis, we found that the strength of the neural representation of the North/South schema for a particular wedding predicted subsequent episodic memory for the details of that wedding.
The genomic landscape of gene-level structural variations in Japanese and global soybean Glycine max cultivars
Japanese soybeans are traditionally bred to produce soy foods such as tofu, miso and boiled soybeans. Here, to investigate their distinctive genomic features, including genomic structural variations (SVs), we constructed 11 nanopore-based genome references for Japanese and other soybean lines. Our assembly-based comparative method, designated ‘Asm2sv’, identified gene-level SVs comprehensively, enabling pangenome analysis of 462 worldwide cultivars and varieties. Based on these, we identified selective sweeps between Japanese and US soybeans, one of which was the pod-shattering resistance gene PDH1. Genome-wide association studies further identified several quantitative trait loci that accounted for large-seed phenotypes of Japanese soybean lines, some of which were also close to regions of the selective sweeps, including PDH1. Notably, specific combinations of alleles, including SVs, were found to increase the seed size of some Japanese landraces. In addition to the differences in cultivation environments, distinct food processing usages might result in changes in Japanese soybean genomes.
Implementing genomic medicine in clinical practice for adults with undiagnosed rare diseases
The global burden of undiagnosed diseases, particularly in adults, is rising due to their significant socioeconomic impact. To address this, we enrolled 232 adult probands with undiagnosed conditions, utilizing bioinformatics tools for genetic analysis. Alongside exome and genome sequencing, repeat-primed PCR and Cas9-mediated nanopore sequencing were applied to suspected short tandem repeat disorders. Probands were classified into probable genetic (n = 128) or uncertain (n = 104) origins. The study found genetic causes in 66 individuals (28.4%) and non-genetic causes in 12 (5.2%), with a longer diagnostic journey for those in the probable genetic group or with pediatric symptom onset, emphasizing the need for increased efforts in these populations. Genetic diagnoses facilitated effective surveillance, cascade screening, drug repurposing, and pregnancy planning. This study demonstrates that integrating sequencing technologies improves diagnostic accuracy, may shorten the time to diagnosis, and enhances personalized management for adults with undiagnosed diseases.
Responses