Biology subjects

Chae, J.-H.

Publications and source records attributed to Chae, J.-H..

4 recordsLinked to original sources

bioRxiv2025

Cas9-enriched nanopore sequencing enables comprehensive and multiplexed detection of repeat expansions

Short tandem repeat (STR) expansion is a major genetic mechanism underlying numerous neurogenetic disorders. However, traditional PCR amplification and short-read next-generation sequencing (NGS)-based methods often fail to detect complex and large expansions including methylation information. Here, we modified an amplification-free nanopore Cas9-targeted sequencing (nCATS) platform and developed a dedicated analysis algorithm, STRiker, for the simultaneous assessment of all currently defined STR loci (56 sites) using a single test with genomic DNA from patient-derived blood cells. We ultimately identified pathogenic repeat expansions in 12 of 37 patients (32.4%) with cerebellar ataxia who remained genetically undiagnosed despite extensive prior genetic testing, in FGF14 (n=4), ATXN8OS, NOP56, RFC1 (n=2 each), and PRNP and NOTCH2NLC (n=1 each). Additionally, family-based cascade screening revealed six relatives with repeat expansions in five families. These results demonstrated a broader diversity of pathogenic repeat structures, particularly in FGF14, and illustrated that CpG methylation can mitigate the pathogenic effects of repeat expansions. This approach offers a powerful strategy for improving the diagnosis of STR-related neurogenetic diseases, for cerebellar ataxia and other STR-related diseases in the future. One Sentence SummaryImproved nanopore Cas9-targeted sequencing with STRiker enhances diagnosis of STR- related neurogenetic diseases and offers broader molecular insights.

bioengineering↗

bioRxiv2024

Inhibiting EZH2 complements steroid effects in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by mutations in the dystrophin gene. Despite recent advances in understanding the disease etiology and applying emerging treatment methodologies, glucocorticoid derivatives remain the only general therapeutic option that can slow disease development. However, the precise molecular mechanism of glucocorticoid action remains unclear, and there is still need for additional remedies to complement the treatment. Here, using single-nucleus RNA-sequencing and spatial transcriptome analyses of human and mouse muscles, we investigated pathogenic features in DMD patients and palliative effects of glucocorticoids. Our approach further illuminated the importance of proliferating satellite cells, and revealed increased activity of a signal transduction pathway involving EZH2 in the patient cells. Subsequent administration of EZH2 inhibitors to Dmd mutant mice resulted in improved muscle phenotype through maintaining the immune-suppressing effect but overriding the muscle weakness and fibrogenic effects exerted by glucocorticoids. Our analysis reveals pathogenic mechanisms that can be readily targeted by extant therapeutic options for DMD. TeaserA survey of DMD tissues in human and mouse suggests EZH2 as a critical factor in DMD satellite cells; its inhibition resulted in better prognosis.

genetics↗

bioRxiv2019

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

BackgroundA substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.\n\nMethodsGenetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.\n\nResultsDisease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.\n\nConclusionsWe suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

genetics↗

bioRxiv2018

Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

ImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).\n\nObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.\n\nDesign, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Childrens Hospital.\n\nExposuresWES of patients and parents and subsequent evaluation of genetic variants.\n\nMain outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.\n\nResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.\n\nConclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?\n\nFindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.\n\nMeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

genetics↗