Sangmoon Lee

Purpose Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS.Materials and Methods This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches.Results TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability, and homologous recombination deficiency scores, which were essential for clinical decision-making.Conclusion TE-WGS is a comprehensive approach in personalized oncology, matching TSO500’s key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Despite the advent of Next-Generation Sequencing (NGS), genetic diagnosis of genetic disorders remains challenging, with diagnostic rates plateauing at approximately 50%. We investigated sensorineural hearing loss (SNHL), a prevalent sensory disorder with substantial genetic heterogeneity, through a comprehensive genomic analysis of a homogeneous disease cohort. Leveraging 394 families (750 individuals), we implemented a systematic multi-tiered genomic approach encompassing single-gene analysis to whole-genome sequencing (WGS), integrated with functional assays and bioinformatic analysis. Our methodological framework revealed a cumulative diagnostic yield of 55.6% (219 families), with automated WGS bioinformatics pipeline uncovering an additional 20 families harboring pathogenic variants, predominantly structural variants. Notably, comparative genomic analysis unveiled a higher frequency of single pathogenic alleles in recessive genes within our SNHL cohort relative to control populations. Subsequent deep intronic region interrogation identified three pathogenic variants on the opposite allele, substantiating the diagnostic utility of comprehensive genomic profiling. Through this approach, we delineated a genome-phenome landscape of SNHL, elucidating molecular signatures and establishing genotype-phenotype correlations at the inner ear functional level. This study underscores the transformative potential of WGS as a robust molecular diagnostic modality, advancing precision medicine paradigms in genetic disease research.

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl , one of several neural tube–expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. While targeted panel sequencing ( TPS ) has been a key clinical tool over the past decade, advancements in sequencing costs and bioinformatics have now made whole-genome sequencing ( WGS ) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) with two primary objectives: 1) assessing actionability for therapeutic options, and 2) providing clarity for clinical questions. Of the 120 various solid cancer patients enrolled, 95 (79%) successfully received genomics reports within a median of 11 working days from sampling to report. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability, and 81% (13/16) to clinical clarity. These benefits encompass selection of informed therapeutics and/or active clinical trials with driver mutations, tumor mutational burden ( TMB ) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and advocate for its integration into routine clinical practice to provide a complete genomic landscape for tailored cancer management.

Cancer poses a significant global health challenge, with increasing incidence rates demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the potential medical application of WGS. Methods This study evaluates the power of target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. A cohort of forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches currently used in the clinic. Results TE-WGS methods detected all the variants reported from TSO500 (100%, 498/498). A high correlation in the detection of variant allele fractions (VAF) was observed between the TE-WGS and TSO500 methodologies (r=0.977). Notably, within the pool of 498 variants commonly detected by both approaches, 223 variants (44.8%) were discerned within peripheral blood samples exclusively through the TE-WGS technique, suggesting their presence as constitutional variants inherent to the germline. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS method, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion-genes, MSI- and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision making. Conclusion TE-WGS proves to be a comprehensive approach in personalized oncology, matching the key biomarker detection capabilities of the established TSO500 panel. Additionally, TE-WGS uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness further underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Objective To evaluate the analytical and clinical performance of the targeted enhanced whole-genome sequencing (TE-WGS) assay for comprehensive genomic profiling in oncology. Methods Analytical validation of the TE-WGS assay focused on sensitivity and specificity for single nucleotide variants (SNVs), insertions and deletions (indels), and structural variants (SVs). Clinical performance was benchmarked against established orthogonal methods for somatic variant detection. Results Analytical validation revealed a sensitivity of 99.8% for SNVs and 98.7% for indels. The positive predictive value (PPV) was 99.3% for SNVs and 98.7% for indels. Clinical validation demonstrated high concordance with reference methods in variant characterization. Conclusion The TE-WGS assay is a clinically valuable tool, providing precise and validated comprehensive genomic profiling that enhances personalized cancer management strategies, with the flexibility to integrate new oncological markers.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy–Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15‐related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy–Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy–Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15‐related disease.

Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients.