Background: As nationwide government-led whole-genome sequencing (WGS) projects progress, optimizing the clinical integration of large-scale WGS results is crucial. We explored how the initial analysis from Korea’s First WGS Pilot Study for Rare Diseases was applied in clinical practice, and then we reanalyzed the data comprehensively at Samsung Medical Center (SMC) Seoul, Korea. Methods: A prospective cohort study designed to collect WGS data under a Korean national initiative was conducted from August 2020 to December 2021. We focused on patients with rare diseases recruited from 16 university hospitals. The participants included 5,000 individuals (2,200 probands and 2,800 family members). The initial WGS data and diagnostic reference reports (from 682 probands and 484 family members), generated based on the First Korean WGS Pilot Study for Rare Diseases, were subsequently reanalyzed by SMC. Results: The initial analysis of the First Korean WGS Pilot Study data revealed a diagnostic rate of 17%. Upon receiving these results, the SMC conducted two rounds of reanalysis, increasing the diagnostic rate from 15% in the first analysis, to 18% in the second, and finally to 24% in the third (P = 1.6 × 10 −5 ). Key factors in improving the genetic diagnosis included increased detection of novel (likely) pathogenic variants (P = 1.0 × 10 −4 ), improved diagnostic rates with larger family recruitment (P = 0.004), and refined clinical information for more precise genotype–phenotype correlation analysis (40%). Conclusions Although national WGS projects lay a foundation for rare disease diagnosis, hospital-level reanalysis and multidisciplinary collaborations are crucial for optimizing diagnostic outcomes.

Background: MUTYH-associated polyposis is an autosomal recessive disorder associated with an increased lifetime risk of colorectal cancer and a moderately increased risk of ovarian, bladder, breast, and endometrial cancers. We analyzed the carrier frequency and estimated the incidence of MUTYH-associated polyposis in East Asian and Korean populations, for which limited data were previously available. Methods: We examined 125,748 exomes from the gnomAD database, including 9,197 East Asians, and additional data from 5,305 individuals in the Korean Variant Archive and 1,722 in the Korean Reference Genome Database. All MUTYH variants were interpreted according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines and the Sequence Variant Interpretation guidelines from ClinGen. Results: The global carrier frequency of MUTYH-associated polyposis was 1.29%, with Europeans (non-Finnish) having the highest frequency of 1.86% and Ashkenazi Jews the lowest at 0.06%. East Asians and Koreans had a carrier frequency of 0.35% and 0.37% and an estimated incidence of 1 in 330,409 and 1 in 293,304 in Koreans, respectively, which were substantially lower than the global average of 1 in 24,160 and the European (nonFinnish) incidence of 1 in 11,520. Conclusions This was the first study to investigate the frequency of carriers of MUTYH-associated polyposis in East Asians, including specific subgroups, utilizing gnomAD and a Korean genome database. Our data provide valuable reference information for future investigations of MUTYH-associated polyposis to understand the genetic diversity and specific variants associated with this condition in East Asian populations.

BACKGROUND/AIMS: We attempted to examine the relationship between abnormal findings on high-resolution manometry (HRM) and videofluoroscopic swallowing study (VFSS) of the pharynx and upper esophageal sphincter (UES), and to identify the risk factors for aspiration. METHODS: We performed VFSS and HRM on the same day in 36 ischemic stroke patients (mean age, 67.5 years) with dysphagia. Pressure (basal, median intra bolus, and nadir), relaxation time interval of the UES, and mesopharyngeal and hypopharyngeal contractility (as a contractile integral) were examined using HRM. The parameters of VFSS were vallecular residue, pyriform sinus residue, vallecular overflow, penetration, and aspiration. The association between the parameters of VFSS and HRM was analyzed by the Student's t test. RESULTS: Three (8.3%) and 4 (11.1%) stroke patients with dysphagia had pyriform sinus residue and vallecular sinus residue, respectively, and 5 (13.8%) patients showed aspiration. Mesopharyngeal and hypopharyngeal contractile integrals in patients with residue in the pyriform sinus were significantly lower than those in patients without residue in the pyriform sinus (P < 0.05). Relaxation time intervals in patients with aspiration were significantly shorter than those in patients without aspiration (P < 0.05), and multivariate regression analysis revealed a shorter relaxation time interval as the main risk factor for aspiration (OR, 0.03; 95% CI, 0.01–0.65; P < 0.05). CONCLUSIONS: Manometric measurements of the pharynx and UES were well correlated with abnormal findings in the VFSS, and a shorter relaxation time interval of the UES during deglutition is an important parameter for the development of aspiration.
Deglutition ; Deglutition Disorders* ; Esophageal Sphincter, Upper* ; Humans ; Manometry ; Pharynx ; Pyriform Sinus ; Relaxation* ; Risk Factors* ; Stroke*

Chromosomal loss in trisomy (trisomy rescue) to generate a disomic fetus can cause confined placental mosaicism and/or feto/placental mosaicism. After trisomy rescue event, there is a risk of fetal uniparental disomy (UPD). Noninvasive prenatal test (NIPT) reflects the genomic constitution of the placenta, not of the fetus itself. Feto-placental discrepancy can therefore cause false-positive (trisomy) NIPT results. These discordant NIPT results can serve as important clues to find UPD associated with confined placental mosaicism. We report a case with maternal UPD of chromosome 20, detected by NIPT of 1,000 high-risk pregnancies, carried out for detecting chromosomal abnormalities in Koreans.
Chromosome Aberrations ; Chromosomes, Human, Pair 20* ; Constitution and Bylaws ; Fetus ; Mosaicism ; Placenta ; Pregnancy, High-Risk* ; Trisomy ; Uniparental Disomy*

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea.
Adult ; Amino Acid Sequence ; Asian Continental Ancestry Group/genetics ; Base Sequence ; DNA/chemistry/genetics/metabolism ; Exons ; Humans ; Male ; Mutation, Missense ; PAX3 Transcription Factor/*genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Republic of Korea ; Sequence Analysis, DNA ; Waardenburg Syndrome/*diagnosis/genetics