The Korean Undiagnosed Diseases Program (KUDP) was launched in January 2017 as a one-year pilot project to address the increasing global interest in patients with undiagnosed rare diseases. The purpose of this paper is to summarize the project results and emphasize the unmet research needs among patients with undiagnosed rare diseases in Korea. Patient enrollment, assessment, and diagnostic processes were determined by the KUDP clinical expert consortium. Patients followed a diagnostic workflow after being categorized into one of four groups: I) insufficient clinical information or lack of standard diagnostic processes; II) undiagnosed due to low disease awareness; III) clinically diagnosed but unconfirmed genetically due to genetic heterogeneities; or IV) unknown disease due to complex, atypical clinical presentations. After excluding two patients from group I, 97 patients were enrolled, including 10 in group II, 67 in group III, and 20 in group IV. Most of them (92 of 97, 94.8%) were pediatric patients (< 18 years old) and 59 (60.8%) were male. The primary symptoms for 80 patients (82.5%) were neurologic. During the one-year pilot study, 72 patients completed a diagnostic assessment including clinical and molecular genetic analyses; some patients also underwent pathological or biochemical analysis. Twenty-eight of these patients (28/72, 38.9%) achieved molecular genetic diagnosis. Thirteen patients were diagnosed based on traditional tests, including biochemical assay, single or targeted genetic analysis, and chromosomal microarray. We performed whole exome sequencing on 52 patients, among whom 15 (28.8%, 15/52) reached a final diagnosis. One new disorder was identified via international collaboration. Using an efficient clinical diagnostic workflow, this KUDP pilot study resulted in a fair diagnostic success rate, improving the potential for additional diagnoses and new scientific discovery of complex and rare diseases. KUDP also satisfied unmet needs for rare diseases with multisystem involvement, highlighting the value of emerging genomic technologies for further research into rare and still-undiagnosed conditions.
Abstract Background A 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. Methods Genetic 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. Results Disease-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. Conclusions We 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.
Abstract Importance Accurate 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). Objective To 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. Design, setting, and participants A 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 Children’s Hospital. Exposures WES of patients and parents and subsequent evaluation of genetic variants. Main outcomes and measures Genetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process. Results We 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. Conclusions and relevance Our 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. Key points Question What 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? Findings Whole 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. Meaning We 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.
<div>AbstractPurpose:<p>The plasticity of innate lymphoid cells (ILCs) has been reported <i>in vitro</i> and in the microenvironment of the intestine. However, whether ILC plasticity contributes to regulation of the tumor microenvironment remains unknown. In this study, we explored plasticity of ILCs in human lung cancer.</p>Experimental Design:<p>We analyzed immune subsets and cytokine expression in lung cancers freshly obtained from 80 patients and explored conversion of ILC1 into ILC3 in coculture with lung cancer cells. Prognostic effects of converted ILC3 and related pathway were evaluated by retrospective cohort composed of 875 patients with lung cancer.</p>Results:<p>Low percentages of ILC1, and high percentages of ILC3 were found in pulmonary squamous cell carcinomas (SqCC) but not adenocarcinomas (ADC). In non–small-cell lung cancers, the percentage of ILC3 was associated with IL23 expression in tumor cells but not immune cells. In cocultures, tumor cells of SqCCs converted ILC1 into ILC3 by producing IL23, thus promoting IL17-mediated tumor cell proliferation. Consistently, among IL17<sup>+</sup> immune cells, the percentages of ILCs were higher in SqCCs than ADCs. Furthermore, the numbers of CD3<sup>−</sup>RORγt<sup>+</sup> ILC3, IL17 expression level, and IL23- or IL17RA-expressing tumor cells were associated with short survival of patients with SqCC but not ADC.</p>Conclusions:<p>Conversion from ILC1 into ILC3 by IL23-producing SqCCs promotes IL17-mediated tumor progression, resulting in a poor prognosis.</p></div>
Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole-exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin-thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.
Glucose transporter type 1 (GLUT1), which is encoded by SLC2A1 (OMIM *138140) on chromosome 1, is a transmembrane transporter that allows glucose to pass through the blood-brain bar-rier.GLUT1 deficiency syndrome (OMIM #606777) is caused by mutations in SLC2A1, which result in hypoglycorrhachia and can limit glucose availability in the brain and lead to cerebral energy deficiency. 1 Since the first description by De Vivo, et al. 2 in 1991, there have been many reports on the wide spectrum of phenotypes of GLUT1 deficiency syndrome.4][5][6][7] However, GLUT1 deficiency syndrome is not easily dichotomized, and is instead recognized as a continuum characterized by phenotypic diversity and evolution with age. 1,4,8Infantile-onset epilepsy can be alleviated during childhood, whereas movement disorders tend to emerge later,
Familial medullary thyroid carcinoma (FMTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. An identifiable RET mutation can be detected in about 85% of FMTC families. The majority of germline mutations in FMTC have been found in exons 10 and 11 of the RET proto-oncogene, specifically within the cysteine codons 609, 611, 618, 620, and 634. We screened members of a large Korean family that had a history of FMTC by genetic analyses, and propose a therapeutic approach for managing the disorder. We report a RET mutation in exon10, codon 618 that causes substitution of a cysteine by a serine in the cysteine-rich domain of the RET receptor in a three-generation FMTC family composed of 30 members with 11 carriers. Nine of the gene carriers were clinically affected. The FMTC with cysteine RET mutations found in the Korean population is consistent with the clinical pattern reported worldwide; to date there have been no ethnic differences identified for FMTC. Our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of MTC.
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