Background/Aims: Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. Methods: Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. Results: Methylome and transcriptome analyses of liver biopsies revealed significant (p<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA<, and SERPING1, as well as hypomethylation (p<0.0005) and upregulation (p<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. Conclusions Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.

Background/Aims: A relationship between fatty liver and lung function impairment has been identified, and both are independently associated with metabolic dysfunction. However, the temporal relationship between changes in fatty liver status and lung function and their genome-wide association remain unclear. Methods: This longitudinal cohort consisted of subjects who received serial health check-ups, including liver ultrasonography and spirometry, for ≥3 years between 2003 and 2015. Lung func-tion decline rates were classified as “slow” and “accelerated” and compared among four different sonographic changes in steatosis status: “normal,” “improved,” “worsened,” and “persistent.” A genome-wide association study was conducted between the two groups: normal/improved steatosis with a slow decline in lung function versus worsened/persistent steatosis with an accelerated decline in lung function. Results: Among 6,149 individuals, the annual rates of decline in forced vital capacity (FVC) and forced expiratory volume measured in the first second of exhalation (FEV 1 ) were higher in the worsened/persistent steatosis group than in the normal/improved steatosis group. In multivariable analysis, persistent or worsened status of fatty liver was significantly associated with accelerated declines in FVC (persistent status, odds ratio [OR]=1.22, 95% confidence interval [CI]=1.04–1.44; worsened status, OR=1.30, 95% CI=1.12–1.50), while improved status of fatty liver was significantly associated with slow declines in FEV 1 (OR=0.77, 95% CI=0.64–0.92). The PNPLA3 risk gene was most strongly associated with steatosis status change and accelerated declines in FVC (rs12483959, p=2.61×10 -7 ) and FEV 1(rs2294433, p=3.69×10 -8 ). Conclusions Regression of fatty liver is related to lung function decline. Continuing efforts to improve fatty liver may preserve lung function, especially for subjects with a high genetic risk.

GLUT1 deficiency is a rare neurometabolic disorder that can be effectively treated with ketogenic diet. However, this condition is underdiagnosed due to its nonspecific, overlapping, and evolving symptoms with age. We retrospectively reviewed the clinical course of nine patients diagnosed with GLUT1 deficiency, based on SLC2A1 mutations and/or glucose concentration in cerebrospinal fluid. The patients included eight boys and one girl who initially presented with seizures (44%, 4/9) or delayed development (44%, 4/9) before 2 years of age, except for one patient who presented with apnea as a neonate. Over the clinical course, all of the children developed seizures of the mixed type, including absence seizures and generalized tonic–clonic seizures. About half (56%, 5/9) showed movement disorders such as ataxia, dystonia, or dyskinesia. We observed an evolution of phenotype over time, although this was not uniform across all patients. Only one child had microcephaly. In five patients, ketogenic diet was effective in reducing seizures and movement symptoms, and the patients exhibited subjective improvement in cognitive function. Diagnosing GLUT1 deficiency can be challenging due to the phenotypic variability and evolution. A high index of clinical suspicion in pediatric and even older patients with epilepsy or movement disorders is key to the early diagnosis and treatment, which can improve the patient's quality of life.
Apnea ; Ataxia ; Cerebrospinal Fluid ; Child ; Clothing ; Cognition ; Dyskinesias ; Dystonia ; Early Diagnosis ; Epilepsy ; Epilepsy, Absence ; Female ; Glucose ; Humans ; Infant, Newborn ; Ketogenic Diet ; Microcephaly ; Movement Disorders ; Phenotype ; Quality of Life ; Retrospective Studies ; Seizures

PURPOSE: Genetic defects in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases were first identified as causes of various disorders in 2007. Variants in IARS2, which encodes a mitochondrial isoleucyl-tRNA synthetase, were first reported in 2014. These variants are associated with diverse phenotypes ranging from CAGSSS (CAtaracts, Growth hormone deficiency, Sensory neuropathy, Sensorineural hearing loss, and Skeletal dysplasia) and Leigh syndrome to isolated nonsyndromic cataracts. Here, we describe the phenotypic and genetic spectrum of Korean patients with IARS2-related disorders. MATERIALS AND METHODS: Using whole-exome sequencing followed by Sanger sequencing, we identified five patients with IARS2 mutations. Their medical records and brain magnetic resonance images were reviewed retrospectively. RESULTS: All five patients presented with developmental delay or regression before 18 months of age. Three patients had bilateral cataracts, but none had hearing loss or sensory neuropathy. No evidence of skeletal dysplasia was noted, but two had short stature. One patient had cardiomyopathy and another exhibited renal tubulopathy and hypoparathyroidism. Their brain imaging findings were consistent with Leigh syndrome. Interestingly, we found the recurrent mutations p.R817H and p.V105Dfs*7 in IARS2. CONCLUSION To our knowledge, this is the first report of Korean patients with IARS2-related disorders. Our findings broaden the phenotypic and genotypic spectrum of IARS2-related disorders in Korea and will help to increase clinical awareness of IARS2-related neurodegenerative diseases.

Point mutations in the human cardiac homeobox gene NKX2.5 are associated with familial atrial septal defect (ASD), atrioventricular (AV) conduction disturbance, as well as sudden cardiac death. To date, more than 60 NKX2.5 mutations have been documented, but there are no reports in Korea. We are reporting the first Korean family with ASD and AV block associated with a novel mutation in the NKX2.5 coding region. A 9-year-old boy presented with a slow and irregular pulse, and was diagnosed with secundum ASD and first degree AV block. The boy's father, who had a history of ASD correction surgery, presented with second degree AV block and atrial fibrillation. The boy's brother was also found to have secundum ASD and first degree AV block. There were two sudden deaths in the family. Genetic testing revealed a novel mutation of NKX2.5 in all affected members of the family.
Atrial Fibrillation ; Atrioventricular Block* ; Child ; Clinical Coding ; Death, Sudden ; Death, Sudden, Cardiac ; Fathers ; Genes, Homeobox ; Genetic Testing ; Heart Septal Defects, Atrial* ; Humans ; Korea ; Male ; Point Mutation ; Siblings

Many cellular structures directly imply specific biological functions. For example, normal slit diaphragm structures that extend from podocyte foot processes ensure the filtering function of renal glomeruli. These slits are covered by a number of surface proteins, such as nephrin, podocin, podocalyxin and CD2AP. Here we report a human patient presenting with congenital nephrotic syndrome, omphalocele and microcoria due to two loss-of-function mutations in PODXL, which encodes podocalyxin, inherited from each parent. This set of symptoms strikingly mimics previously reported mouse Podxl(−/−) embryos, emphasizing the essential function of PODXL in mammalian kidney development and highlighting this patient as a human PODXL-null model. The results underscore the utility of current genomics approaches to provide insights into the genetic mechanisms of human disease traits through molecular diagnosis.

Ethnically specific data on genetic variation are crucial for understanding human biology and for clinical interpretation of variant pathogenicity. We analyzed data obtained by deep sequencing 1303 Korean whole exomes; the data were generated by three independent whole exome sequencing projects (named the KOEX study). The primary focus of this study was to comprehensively analyze the variant statistics, investigate secondary findings that may have clinical actionability, and identify loci that should be cautiously interpreted for pathogenicity. A total of 495 729 unique variants were identified at exonic regions, including 169 380 nonsynonymous variants and 4356 frameshift insertion/deletions. Among these, 76 607 were novel coding variants. On average, each individual had 7136 nonsynonymous single-nucleotide variants and 74 frameshift insertion/deletions. We classified 13 pathogenic and 13 likely pathogenic variants in 56 genes that may have clinical actionability according to the guidelines of the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology. The carrier frequency of these 26 variants was 2.46% (95% confidence interval 1.73–3.46). To identify loci that require cautious interpretation in clinical sequencing, we identified 18 genes that are prone to sequencing errors, and 671 genes that are highly polymorphic and carry excess nonsynonymous variants. The catalog of identified variants, its annotation and frequency information are publicly available (https://koex.snu.ac.kr). These findings should be useful resources for investigating ethnically specific characteristics in human health and disease.
Biology ; Clinical Coding ; Exome ; Exons ; Genetic Variation ; Genetics, Medical ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Pathology, Molecular ; Virulence

OBJECTIVE: The Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) aimed to recruit 650 individuals, aged from 20 to 90 years, to search for new biomarkers of Alzheimer's disease (AD) and to investigate how multi-faceted lifetime experiences and bodily changes contribute to the brain changes or brain pathologies related to the AD process. METHODS: All participants received comprehensive clinical and neuropsychological evaluations, multi-modal brain imaging, including magnetic resonance imaging, magnetic resonance angiography, [11C]Pittsburgh compound B-positron emission tomography (PET), and [18F]fluorodeoxyglucose-PET, blood and genetic marker analyses at baseline, and a subset of participants underwent actigraph monitoring and completed a sleep diary. Participants are to be followed annually with clinical and neuropsychological assessments, and biannually with the full KBASE assessment, including neuroimaging and laboratory tests. RESULTS: As of March 2017, in total, 758 individuals had volunteered for this study. Among them, in total, 591 participants–291 cognitively normal (CN) old-aged individuals, 74 CN young- and middle-aged individuals, 139 individuals with mild cognitive impairment (MCI), and 87 individuals with AD dementia (ADD)–were enrolled at baseline, after excluding 162 individuals. A subset of participants (n=275) underwent actigraph monitoring. CONCLUSION: The KBASE cohort is a prospective, longitudinal cohort study that recruited participants with a wide age range and a wide distribution of cognitive status (CN, MCI, and ADD) and it has several strengths in its design and methodologies. Details of the recruitment, study methodology, and baseline sample characteristics are described in this paper.
Aging* ; Alzheimer Disease* ; Biomarkers ; Brain* ; Cohort Studies ; Dementia ; Early Diagnosis* ; Genetic Markers ; Magnetic Resonance Angiography ; Magnetic Resonance Imaging ; Mild Cognitive Impairment ; Neuroimaging ; Pathology ; Prospective Studies

Since next-generation sequencing (NGS) technique was adopted into clinical practices, revolutionary advances in diagnosing rare genetic diseases have been achieved through translating genomic medicine into precision or personalized management. Indeed, several successful cases of molecular diagnosis and treatment with personalized or targeted therapies of rare genetic diseases have been reported. Still, there are several obstacles to be overcome for wider application of NGS-based precision medicine, including high sequencing cost, incomplete variant sensitivity and accuracy, practical complexities, and a shortage of available treatment options.
Diagnosis ; Humans ; Precision Medicine* ; Rare Diseases ; Translating