• Journal of Genetic Medicine
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• v.15 no.2
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• pp.92-96
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• 2018

Chronic mucocutaneous candidiasis (CMC) is characterized by increased susceptibility to chronic and recurrent infections of the skin, mucous membranes, and nails by Candida species. It is a primary immunodeficiency disorder that is difficult to diagnose because of its heterogeneous clinical manifestations and genetic background. A 20-month-old boy who did not grow in height for 3 months was diagnosed as having hypothyroidism and he had hepatitis which was found at 5 years old. He presented with persistent oral thrush and vesicles on the body, the cause of which could not be identified from laboratory findings. No microorganism was detected in the throat culture; however, the oral thrush persisted. Immunological tests showed that immunoglobulin (Ig) subclass IgG and cluster of differentiation (CD)3, CD4, and CD8 levels were within normal limits. We prescribed oral levothyroxine and fluconazole mouth rinse. The patient was examined using diagnostic exome sequencing at the age of 6 years, and a c.1162A>G (p.K388E) STAT1 gene mutation was identified. A diagnosis of CMC based on the STAT1 gene mutation was, thus, made. At the age of 8 years, the boy developed a malar-like rash on his face. We conducted tests for detection of antinuclear antibodies and anti-dsDNA antibodies, which showed positive results; therefore, systemic lupus erythematosus (SLE) was also suspected. Whole exome sequencing is important to diagnose rare diseases in children. A STAT1 gene mutation should be suspected in patients with chronic fungal infections with a thyroid disease and/or SLE.

• Asian-Australasian Journal of Animal Sciences
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• v.32 no.12
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• pp.1826-1835
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• 2019

Objective: Testicular growth and development are strongly influenced by androgen. Although both testis weight and plasma testosterone level are inherited traits, the interrelationship between them is not fully established. Males of DDD/Sgn (DDD) mice are known to have extremely heavy testes and very high plasma testosterone level among inbred mouse strains. We dissected the genetic basis of testis weight and analyzed the potential influence of plasma testosterone level in DDD mice. Methods: Quantitative trait loci (QTL) mapping of testis weight was performed with or without considering the influence of plasma testosterone level in reciprocal $F_2$ intercross populations between DDD and C57BL/6J (B6) mice, thereby assessing the influence of testosterone on the effect of testis weight QTL. Candidate genes for testis weight QTL were investigated by next-generation sequencing analysis. Results: Four significant QTL were identified on chromosomes 1, 8, 14, and 17. The DDDderived allele was associated with increased testis weight. The $F_2$ mice were then divided into two groups according to the plasma testosterone level ($F_2$ mice with relatively "low" and "high" testosterone levels), and QTL scans were again performed. Although QTL on chromosome 1 was shared in both $F_2$ mice, QTL on chromosomes 8 and 17 were identified specifically in $F_2$ mice with relatively high testosterone levels. By whole-exome sequencing analysis, we identified one DDD-specific missense mutation Pro29Ser in alpha tubulin acetyltransferase 1 (Atat1). Conclusion: Most of the testis weight QTL expressed stronger phenotypic effect when they were placed on circumstance with high testosterone level. High testosterone influenced the QTL by enhancing the effect of DDD-derived allele and diminishing the effects of B6-derived allele. Since Pro29Ser was not identified in other inbred mouse strains, and since Pro29 in Atat1 has been strongly conserved among mammalian species, Atat1 is a plausible candidate for testis weight QTL on chromosome 17.

• Journal of Genetic Medicine
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• v.18 no.1
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• pp.64-69
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• 2021

Primary cilium has a signal transduction function that is essential for brain development, and also determines cell polarity and acts as a mediator for important signaling systems, especially the Sonic Hedgehog (SHH) pathway. TBC1D32 is a ciliary protein, implicated in SHH signaling. Biallelic mutations in the TBC1D32 gene causes a kind of ciliopathy, heterogeneous developmental or degenerative disorders that affect multiple organs, including the brain. Here we report a boy who carried compound heterozygous variants in TBC1D32. The patient showed hypotonia, respiratory difficulty, and multiple anomalies at his birth. He was diagnosed with congenital hypopituitarism and treated with T4, hydrocortisone, and growth hormone. Despite the hormonal replacement, the patient needed long-term respiratory support with tracheostomy and nutritional support with a feeding tube. His developmental milestones were severely retarded. Hydrocephalus and strabismus developed and both required surgery, during the outpatient follow-up. Whole-exome sequencing indicated compound heterozygous variants, c.2200C>T (p.Arg734^*) and c.156-1G>T, in TBC1D32 gene. This is the first Korean case of TBC1D32-related ciliopathy and we reported detailed and sequential clinical features. This case demonstrated the utility of whole-exome sequencing and provided valuable clinical data on ultra-rare disease.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.25 no.6
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• pp.441-452
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• 2022

Congenital diarrheal disorders (CDDs) with genetic etiology are uncommon hereditary intestinal diseases characterized by chronic, life-threatening, intractable watery diarrhea that starts in infancy. CDDs can be mechanistically divided into osmotic and secretory diarrhea. Congenital tufting enteropathy (CTE), also known as intestinal epithelial dysplasia, is a type of secretory CDD. CTE is a rare autosomal recessive enteropathy that presents with intractable neonatal-onset diarrhea, intestinal failure, severe malnutrition, and parenteral nutrition dependence. Villous atrophy of the intestinal epithelium, crypt hyperplasia, and irregularity of surface enterocytes are the specific pathological findings of CTE. The small intestine and occasionally the colonic mucosa include focal epithelial tufts. In 2008, Sivagnanam et al. discovered that mutations in the epithelial cell adhesion molecule (EpCAM, MIM# 185535) were the genetic cause of CTE (MIM# 613217). More than a hundred mutations have been reported to date. Furthermore, mutations in the serine peptidase inhibitor Kunitz type 2 (SPINT2, MIM# 605124) have been linked to syndromic CTE. In this study, we report the case of a 17-month-old male infant with congenital diarrhea. Despite extensive etiological workup, no etiology could be established before admission to our center. The patient died 15 hours after being admitted to our center in a metabolically decompensated state, probably due to a delay in admission and diagnosis. Molecular autopsy with exome sequencing revealed a previously reported homozygous missense variant, c.757G>A, in EpCAM, which was confirmed by histopathological examination.

• Journal of the Korean neurological association
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• v.30 no.4
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• pp.333-336
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• 2012

Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene is known to be associated with different clinical phenotypes; Silver syndrome, Charcot-Marie-Tooth type 2 with a dominant hand involvement and distal hereditary motor neuropathy type V (dHMN-V). Up to now, only two heterozygous mutations (N88S and S90L) in BSCL2 have been reported. We identified a N88S BSCL2 mutation in a dHMN-V family with a spastic gait by whole-exome sequencing. To our knowledge, this is the first report of a N88S BSCL2 mutation in Korean patient.

• Journal of Interdisciplinary Genomics
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• v.3 no.2
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• pp.41-46
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• 2021

Inherited platelet function disorders (IPFDs) are a disease group of heterogeneous bleeding disorders associated with congenital defects of platelet functions. Normal platelets essential role for primary hemostasis by adhesion, activation, secretion of granules, aggregation, and procoagulant activity of platelets. The accurate diagnosis of IPFDs is challenging due to unavailability of important testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. Among several IPFDs, Glanzmann thrombasthenia (GT) is a most representative IPFD and is relatively frequently found compare to the other types of rarer IPFDs. GT is an autosomal recessive disorder caused by mutations of ITGA2B or ITGB3. There are quantitative or qualitative defects of the GPIIb/IIIa complex in platelet, which is the binding receptor for fibrinogen, von Willbrand factor, and fibronectin in GT patients. Therefore, patients with GT have normal platelet count and normal platelet morphology, but they have severely decreased platelet aggregation. Thus, GT patients have a very severe hemorrhagic phenotypes that begins at a very early age and persists throughout life. In this article, the general contents about platelet functions and respective IPFDs, the overall contents of GT, and the current status of genetic diagnosis of GT in Korea will be reviewed.

• The Journal of the Korea Contents Association
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• v.22 no.2
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• pp.762-769
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• 2022

Genetic testing in prenatal diagnosis is a precious tool providing valuable information in clinical management and parental decision-making. For the last year, cytogenetic testing methods, such as G-banding karyotype analysis, fluorescent in situ hybridization, chromosomal microarray, and gene panels have evolved to become part of routine laboratory testing. However, the limitations of each of these methods demonstrate the need for a revolutionary technology that can alleviate the need for multiple technologies. The recent introduction of new genomic technologies based on next-generation sequencing has changed the current practice of prenatal testing. The promise of these innovations lies in the fast and cost-effective generation of genome-scale sequence data with exquisite resolution and accuracy for prenatal diagnosis. Here, we review the current state of sequencing-based pediatric diagnostics, associated challenges, as well as future prospects.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.20 no.2
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• pp.114-123
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• 2017

Purpose: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. Methods: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. Results: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. Conclusion: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.

• Genomics & Informatics
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• v.15 no.1
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• pp.48-50
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• 2017

Tumor tissues from biopsies or surgery are major sources for the next generation sequencing (NGS) study, but these procedures are invasive and have limitation to overcome intratumor heterogeneity. Recent studies have shown that driver alterations in tumor tissues can be detected by liquid biopsy which is a less invasive technique capable of both capturing the tumor heterogeneity and overcoming the difficulty in tissue sampling. However, it is still unclear whether the driver alterations in liquid biopsy can be detected by targeted NGS and how those related to the tissue biopsy. In this study, we performed whole-exome sequencing for a breast cancer tissue and identified PTEN p.H259fs*7 frameshift mutation. In the plasma DNA (liquid biopsy) analysis by targeted NGS, the same variant initially identified in the tumor tissue was also detected with low variant allele frequency. This mutation was subsequently validated by digital polymerase chain reaction in liquid biopsy. Our result confirm that driver alterations identified in the tumor tissue were detected in liquid biopsy by targeted NGS as well, and suggest that a higher depth of sequencing coverage is needed for detection of genomic alterations in a liquid biopsy.

• Journal of Genetic Medicine
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• v.16 no.1
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• pp.19-22
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• 2019

The infantile convulsions and choreoathetosis (ICCA) syndrome is defined when two overlapping clinical features of benign familial infantile epilepsy (BFIE) and paroxysmal kinesigenic dyskinesia (PKD) are present in an individual or a family. Since the gene encoding proline-rich transmembrane protein 2 (PRRT2) was first identified in Han Chinese families with PKD, mutations of PRRT2 have additionally been reported in patients with BFIE and ICCA. We attempted to identify the genetic etiology in an ICCA family where the proband, her elder sister, and a maternal male cousin had BFIE, and her mother had PKD. Whole-exome sequencing performed in the proband and her sister and mother identified a novel pathogenic mutation of PRRT2 (c.640delinsCC; p.Ala214ProfsTer11), which was verified by Sanger sequencing. This frameshift PRRT2 mutation located near the genetic hot spot of base 649_650 results in the premature termination of the protein, as do most previously reported mutations in BFIE, ICCA, and PKD.