Jung Min Ko

Background and ObjectivesKleefstra syndrome type 1 (KLEFS1) is a rare neurodevelopmental disorder caused by pathogenic variants in EHMT1, which play a key role in epigenetic regulation. Core featur...

Genomic newborn screening (NBS) has emerged as a powerful complement to conventional screening; however, its clinical utility remains to be fully established. We conducted a prospective multicenter pilot study within the Seoul National University Hospital network from November 2025 to February 2026. A panel of 419 genes was curated by a multidisciplinary expert team based on early childhood onset, disease severity, the presence of an asymptomatic window, and the local availability of effective treatments. Genome sequencing was performed on 399 newborns, including six monozygotic twin pairs analyzed as single data points. In addition to 385 inborn neonates, 14 neonates referred because of abnormal conventional NBS results were included. As a result, the screen-positive rate was 1.3% (5/393). Two positive cases with variants in SLC25A15 and MYO15A were missed by conventional NBS, and we also identified three cases harboring pathogenic variants in arrhythmia-associated genes, a category inherently beyond the scope of conventional screening. Among 49 neonates with abnormal conventional NBS results, all were negative on genomic NBS. The median turnaround time from sample collection to final report was 26 days. Genomic NBS demonstrated favorable precision and complementary clinical utility beyond conventional screening. Regular multidisciplinary curation of target genes and long-term longitudinal follow-up are essential for successful clinical implementation.

Background: Protective parental behavior is crucial for children’s safety and emotional well-being, but excessive protection may hinder their autonomy. This issue is particularly relevant for caregivers of children with chronic or rare diseases, who may adopt heightened protective behaviors. The Parent Protection Scale (PPS) is a validated patient-reported tool for assessing parental overprotection. Given Korea’s unique cultural context, which emphasizes close family ties, this study aimed to translate and validate PPS for Korean populations. Methodology: A total of 179 caregivers of pediatric patients aged 5–10 years with cancer or rare diseases were recruited from eight hospitals across Korea between August 2023 and December 2024. The PPS was translated into Korean through a forward-backward translation process. Exploratory factor analysis (EFA) with principal axis factoring and direct oblimin rotation was performed to examine the factor structure. Internal consistency was assessed by Cronbach’s alpha, and concurrent validity was evaluated using Pearson correlation with questionnaires for anxiety, depression, and social support measures. Results: EFA revealed a four-factor structure, which differed from that of the original PPS subscales—strict behavioral control, emotional intrusiveness, anxious ambivalence, and autonomy restriction—accounting for 44.85% of the total variance. Internal consistency was acceptable for the total scale (α = 0.79) and moderate for two subscales (anxious ambivalence and autonomy restriction; α = 0.66–0.75) but lower for the others (strict behavioral control and emotional intrusiveness; α = 0.57–0.64). Significant negative correlations were found between strict behavioral control, anxious ambivalence, and autonomy restriction and caregiver anxiety, depression, and social support, supporting concurrent validity. No significant associations were observed between emotional intrusiveness and caregiver anxiety, depression, or social support. Conclusions: This study provides evidence that the Korean PPS is a culturally adapted tool with acceptable overall reliability for assessing parental protection, with the potential to inform family-centered care and culturally adapted interventions. In clinical practice, it may support more precise identification of protective parenting patterns and guide targeted interventions to balance protection with the promotion of child autonomy.

Enzyme replacement therapy (ERT) with elosulfase alfa is the only approved treatment for mucopolysaccharidosis type IVA. This case report delineates the 5‐year outcomes of ERT in two Korean siblings with mucopolysaccharidosis type IVA, with the younger sibling initiating treatment at 0.8 years of age and the older one at 5.4 years. Both patients exhibited a progressive decline in their height standard deviation scores, with trajectories paralleling the natural history curves of the disease. At 5.2 years of age, persistent skeletal dysplasia was evident in both siblings. However, the younger sibling demonstrated attenuated disease severity, lacking cervical myelopathy or spinal stenosis requiring C1 laminoplasty. Cardiorespiratory assessment revealed normalized left ventricular mass index z‐scores, stable ejection fractions, and the absence of valvular pathology. Overall, these findings suggest that early ERT attenuates severe spinal and upper body manifestations but does not prevent lower limb skeletal progression, highlighting the need for early therapeutic initiation along with orthopedic intervention to preserve cardiorespiratory parameters and functional independence.

Short-read sequencing (SRS)-based disease-targeted NGS gene panels have revolutionized rare disease diagnostics but often leave autosomal recessive cases unsolved when only one pathogenic allele is detected. Missing variants may reside in deep intronic regions or involve structural variants (SVs) undetectable by SRS. To improve diagnostic yield, we implemented a cost-effective target capture-based long-read sequencing (LRS) assay covering 56 genes and retrospectively analyzed 78 patients suspected of autosomal recessive disorders who remained undiagnosed after SRS. Functional validation using reverse transcription PCR (RT-PCR) and minigene assays was performed to further determine pathogenicity. Target capture-based LRS solved 25.6% (20/78) of cases by identifying 10 SVs, 3 deep intronic variants experimentally confirmed to cause aberrant splicing, and 7 cases in which haplotype phasing confirmed that variants were in trans with the known pathogenic variant, leading to reclassification of the VUS as likely pathogenic. This study demonstrates that target capture-based LRS effectively detects diverse types of variants missed by SRS. Integrating this assay into stepwise diagnostic workflows offers a practical and cost-effective strategy to enhance diagnostic yield in autosomal recessive diseases. However, because this cohort was retrospectively defined based on a prior single-allele detection by SRS, this 25.6% (20/78) diagnostic yield reflects performance within a highly enriched population and should not be directly extrapolated to unselected rare disease cohorts.

Global developmental delay (GDD) and intellectual disability (ID) are frequently caused by genetic factors, yet many patients remain undiagnosed even after whole exome sequencing (WES). This study aimed to apply Optical Genome Mapping (OGM) and Illumina Complete Long Reads (ICLR) in pediatric patients with unexplained GDD/ID after WES and propose a practical diagnostic strategy for clinical implementation. We conducted OGM and ICLR on 87 pediatric patients with unexplained GDD/ID despite prior WES. Discordant cases underwent further validation using gap-PCR or PacBio long-read sequencing. A minigene assay was also performed to confirm the pathogenicity of an intronic variant. Of the 87 patients, 6 were found to carry pathogenic or likely pathogenic variants, including 4 structural variants (SVs) and 2 single nucleotide variants (SNVs). OGM and ICLR provided additional diagnostic yields of 4.71% and 6.98%. OGM was effective in detecting complex rearrangements, whereas ICLR performed well in cases with overlapping structural variants. For all SV burden, ICLR detected 8 SVs (mean 0.09 ± 0.33 per sample), and OGM identified 8 SVs (mean 0.09 ± 0.29 per sample), showing comparable results. This study demonstrates the complementary utility of ICLR and OGM in detecting diverse classes of pathogenic variants in GDD/ID. ICLR was advantageous for detecting non-coding SNVs, as well as for providing accurate breakpoint resolution in SVs, while OGM was effective for complex rearrangements and repetitive regions. These findings support a stepwise diagnostic strategy in which ICLR may be considered as an early second-tier test for WES-negative GDD/ID cases.