• Genomics & Informatics
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• v.13 no.4
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• pp.126-131
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• 2015

Fulminant type 1 diabetes (T1DM) is a distinct subtype of T1DM that is characterized by rapid onset hyperglycemia, ketoacidosis, absolute insulin deficiency, and near normal levels of glycated hemoglobin at initial presentation. Although it has been reported that class II human leukocyte antigen (HLA) genotype is associated with fulminant T1DM, the genetic predisposition is not fully understood. In this study we investigated the HLA genotype and haplotype in 11 Korean cases of fulminant T1DM using imputation of whole exome sequencing data and compared its frequencies with 413 participants of the Korean Reference Panel. The $HLA-DRB1^*04:05-HLA-DQB1^*04:01$ haplotype was significantly associated with increased risk of fulminant T1DM in Fisher's exact test (odds ratio [OR], 4.11; 95% confidence interval [CI], 1.56 to 10.86; p = 0.009). A histidine residue at $HLA-DR{\beta}1$ position 13 was marginally associated with increased risk of fulminant T1DM (OR, 2.45; 95% CI, 1.01 to 5.94; p = 0.054). Although we had limited statistical power, we provide evidence that HLA haplotype and amino acid change can be a genetic risk factor of fulminant T1DM in Koreans. Further large-scale research is required to confirm these findings.

• Genes and Genomics
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• v.40 no.11
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• pp.1149-1155
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• 2018

Epileptic encephalopathies are genetically heterogeneous disorders which leads to epilepsy and cause neurological disorders. Seizure threshold 2 (SZT2) gene located on chromosome 1p34.2 encodes protein mainly expressed predominantly in the parietal and frontal cortex and dorsal root ganglia in the brain. Previous studies in mice showed that mutation in this gene can confers low seizure threshold, enhance epileptogenesis and in human may leads to facial dysmorphism, intellectual disability, seizure and macrocephaly. Objective of this study was to find out novel gene or novel mutation related to the gene phenotype. We have identified a large consanguineous Saudi family segregating developmental delay, intellectual disability, epilepsy, high forehead and macrocephaly. Exome sequencing was performed in affected siblings of the family to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation study. Our results showed a novel homozygous mutation (c.9368G>A) in a substitution of a conserved glycine residue into a glutamic acid in the exon 67 of SZT2 gene. The mutation was ruled out in 100 unrelated healthy controls. The missense variant has not yet been reported as pathogenic in literature or variant databases. In conclusion, the here detected homozygous SZT2 variant might be the causative mutation that further explain epilepsy and developmental delay in this Saudi family.

• Journal of Genetic Medicine
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• v.15 no.2
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• pp.102-106
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• 2018

Aggrecan is a proteoglycan in the extracellular matrix of growth plate and cartilaginous tissues. Aggrecanopathy has been reported as a genetic cause not only for severe skeletal dysplasia but also for autosomal dominant short stature with normal to advanced bone age. We report a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature identified through targeted exome sequencing. We present a girl of 4 years and 9 months with a family history of short stature over three generations. The paternal grandmother is 143 cm tall (-3.8 as a Korean standard deviation score [SDS]), the father 155 cm (-3.4 SDS), and the index case 96.2 cm (-2.9 SDS). Evaluation for short stature showed normal growth hormone (GH) peaks in the GH provocation test and a mild delayed bone age for chronological age. This subject had clinical characteristics including a triangular face, flat nasal bridge, prognathia, blue sclerae, and brittle teeth. The targeted exome sequencing was applied to detect autosomal dominant growth palate disorder. The novel variant c.910G>A (p.Asp304Asn) in ACAN was identified and this variant was found in the subject's father using Sanger sequencing. This is the first case of Korean familial short stature due to ACAN mutation. ACAN should be considered for proportionate idiopathic short stature, especially in cases of familial short stature.

• 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.

• Journal of Yeungnam Medical Science
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• v.38 no.2
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• pp.160-164
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• 2021

Oculocutaneous albinism (OCA) is a group of rare genetically heterogeneous disorders, characterized by hypopigmentation of the eyes, skin, and hair, which result in ocular abnormalities and a risk of developing skin cancer. Currently, there is no ophthalmologic procedure or drug that prevents the clinical features of OCA. Here, we report a new type of OCA in two, unrelated Korean families with the same OCA2 mutation. Affected individuals in this study are different from those of previous reports in two aspects: an inheritance pattern and clinical presentation. All reported patients with OCA have shown an autosomal recessive inheritance pattern, while our patients showed an autosomal dominant inheritance pattern. Small amounts of pigment can be acquired with age in OCA, but there is no substantial variation from adolescence to adulthood in this regard. A case where the patient attained normal pigmentation levels has never been reported. However, our patients displayed completely normal pigmentation in their late twenties. Whole exome sequencing and in-silico analysis revealed a novel mutation, OCA2 c.2338G>A p.(G780S) (NM_000275) with a high likelihood of pathogenicity. Sanger sequencing of p.G780S identified the same mutation in the affected individuals, which was not found in the family members with normal phenotype. We hypothesize that OCA2 G780S not only acts as a pathogenic variant of OCA but also induces pigmentation by enhancing the melanogenesis gene expression of other modifier genes, such as SLC45A2 and TPC2. These findings may provide further understanding of melanin biosynthesis and new treatment methods for OCA.

• 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.

• Genomics & Informatics
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• v.14 no.2
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• pp.42-45
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• 2016

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.

• Journal of Genetic Medicine
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• v.15 no.2
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• pp.107-109
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• 2018

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is caused by the mutation in GJB1 gene, characterized by the transient central nervous system involvement and long standing peripheral polyneuropathy which does not fulfill the criteria of demyelination or axonopathy. We describe a 37-year-old man with progressive bilateral leg weakness since his early teen. He suffered transient right hemiparesis, followed by quadriparesis at 14 years of age. When we examined him at 37 years of age, he presented a distal muscle weakness on lower extremities with a sensory symptom. The nerve conduction study demonstrated a motor conduction velocity between 26 and 49 m/s. The whole exome sequencing revealed a novel variant c.136 G>A in GJB1. This report will raise awareness in this rare disease, which is frequently misdiagnosed early in its course.