• Journal of Gastric Cancer
• /
• v.20 no.1
• /
• pp.29-40
• /
• 2020

Purpose: Gastrointestinal stromal tumors (GISTs) frequently harbor activating gene mutations in either KIT or platelet-derived growth factor receptor A (PDGFRA) and are highly responsive to several selective tyrosine kinase inhibitors. In this study, a targeted next-generation sequencing (NGS) assay with an Oncomine Focus Assay (OFA) panel was used for the genetic characterization of molecular targets in 30 Korean patients with GIST. Materials and Methods: Using the OFA that enables rapid and simultaneous detection of hotspots, single nucleotide variants (SNVs), insertion and deletions (Indels), copy number variants (CNVs), and gene fusions across 52 genes relevant to solid tumors, targeted NGS was performed using genomic DNA extracted from formalin-fixed and paraffin-embedded samples of 30 GISTs. Results: Forty-three hotspot/other likely pathogenic variants (33 SNVs, 8 Indels, and 2 amplifications) in 16 genes were identified in 26 of the 30 GISTs. KIT variants were most frequent (44%, 19/43), followed by 6 variants in PIK3CA, 3 in PDGFRA, 2 each in JAK1 and EGFR, and 1 each in AKT1, ALK, CCND1, CTNNB1, FGFR3, FGFR4, GNA11, GNAQ, JAK3, MET, and SMO. Based on the mutation types, majority of the variants carried missense mutations (60%, 26/43), followed by 8 frameshifts, 6 nonsense, 1 stop-loss, and 2 amplifications. Conclusions: Our study confirmed the advantage of using targeted NGS with a cancer gene panel to efficiently identify mutations associated with GISTs. These findings may provide a molecular genetic basis for developing new drugs targeting these gene mutations for GIST therapy.

• Clinical and Experimental Pediatrics
• /
• v.61 no.4
• /
• pp.101-107
• /
• 2018

Recent advances in genetics have determined that a number of epilepsy syndromes that occur in the first year of life are associated with genetic etiologies. These syndromes range from benign familial epilepsy syndromes to early-onset epileptic encephalopathies that lead to poor prognoses and severe psychomotor retardation. An early genetic diagnosis can save time and overall cost by reducing the amount of time and resources expended to reach a diagnosis. Furthermore, a genetic diagnosis can provide accurate prognostic information and, in certain cases, enable targeted therapy. Here, several early infantile epilepsy syndromes with strong genetic associations are briefly reviewed, and their genotype-phenotype correlations are summarized. Because the clinical presentations of these disorders frequently overlap and have heterogeneous genetic causes, next-generation sequencing (NGS)-based gene panel testing represents a more powerful diagnostic tool than single gene testing. As genetic information accumulates, genetic testing will likely play an increasingly important role in diagnosing pediatric epilepsy. However, the efforts of clinicians to classify phenotypes in nondiagnosed patients and improve their ability to interpret genetic variants remain important in the NGS era.

• Journal of Genetic Medicine
• /
• v.16 no.2
• /
• pp.62-66
• /
• 2019

Harlequin ichthyosis (HI, OMIM #242500) is one of the most severe skin diseases among the autosomal recessive congenital ichthyoses, with high morbidity and mortality, particularly in newborns. Clinically, it is characterized by a typical appearance of generalized, thick, yellowish, hyperkeratotic plates with deep erythematous fissures on the skin. Herein, we present the case of a newborn girl with HI that was genetically confirmed by targeted gene panel analysis. The premature baby was encased in an opaque white membrane with erosion covering the skin of the entire body except the lips, with her hands and feet restricted by the membrane. Humidification, emollient, and retinoic acid treatment were started; the thick ichthyosis gradually peeled off and the underlying skin was only covered with thin scales. Targeted gene panel analysis using next-generation sequencing and validation with Sanger sequencing and quantitative polymerase chain reaction analyses confirmed compound heterozygous mutations of the ABCA12 gene (p.N1380S and a partial gene deletion encompassing exon 9). The parents were carriers for each of the identified mutations. Early recognition of the genetic etiology of congenital ichthyosis can, thus, facilitate genetic counseling for patients and their families.

• Journal of Genetic Medicine
• /
• v.15 no.2
• /
• pp.110-114
• /
• 2018

Ataxia-telangiectasia (AT; OMIM 208900) is a rare autosomal recessive inherited progressive neurodegenerative disorder, with onset in early childhood. AT is caused by homozygous or compound heterozygous mutations in ATM (OMIM 607585) on chromosome 11q22. The average prevalence of the disease is estimated at 1 of 100,000 children worldwide. The prevalence of AT in the Republic of Korea is suggested to be extremely low, with only a few cases genetically confirmed thus far. Herein, we report a 5-year-old Korean boy with clinical features such as progressive gait and truncal ataxia, both ankle spasticity, dysarthria, and mild intellectual disability. The patient was identified as a compound heterozygote with two novel genetic variants: a paternally derived c.5288_5289insGA p.(Tyr1763*) nonsense variant and a maternally derived c.8363A>C p.(His2788Pro) missense variant, as revealed by next-generation sequencing and confirmed by Sanger sequencing. Based on claims data from the Health Insurance Review and Assessment Service Republic of Korea, we calculated the prevalence of AT in the Republic of Korea to be about 0.9 per million individuals, which is similar to the worldwide average. Therefore, we suggest that multi-gene panel sequencing including ATM should be considered early diagnosis.

• Journal of Genetic Medicine
• /
• v.17 no.1
• /
• pp.34-38
• /
• 2020

The term dopa-responsive dystonia (DRD) is used to describe a group of neurometabolic disorders, which are characterized by dystonia, and are typically associated with diurnal fluctuations and respond to levodopa treatment. Autosomal dominant DRD (DYT5a, MIM# 128230) is caused by a heterozygous mutation in the GTP cyclohydrolase 1 (GCH1) gene (MIM# 600225). GCH1 encodes an enzyme, which is involved in the biosynthesis of tetrahydrobiopterin, an essential co-factor for tyrosine hydroxylase. Herein, we report the case of a 16-year-old girl who was diagnosed with DYT5a. She exhibited additional unusual clinical features, including intellectual disability, depression, multiple skeletal anomalies, and short stature, which are not commonly observed in patients with DYT5a. The patient harbored a heterozygous missense variant, c.539A>C, p.Gln180Pro, in the GCH1 gene, which was identified by targeted gene panel analysis using next-generation sequencing.

• Journal of Genetic Medicine
• /
• v.15 no.2
• /
• pp.97-101
• /
• 2018

Tricho-rhino-phalangeal syndrome (TRPS) is a hereditary disorder characterized by craniofacial and skeletal abnormalities. A mutation of the TRPS1 gene leads to TRPS type I or type III. A 20-year-old male patient visited our neurologic department with chronic fatigue. He presented with short stature, sparse hair, pear-shaped nose, and brachydactyly. Radiologic study showed short metacarpals, metatarsals with cone-shaped epiphyses, hypoplastic femur and hip joint. Panel sequencing for OMIM (Online Mendelian Inheritance in Man) listed genes revealed a de novo heterozygous frameshift mutation of c.1801_1802delGA (p.Arg601Lysfs*3) of exon 4 of the TRPS1 gene. The diagnosis of TRPS can be challenging due to the rarity and variable phenotype of the disease, clinicians should be aware of its characteristic clinical features that will lead a higher rate of diagnosis.

• Asian-Australasian Journal of Animal Sciences
• /
• v.23 no.1
• /
• pp.7-12
• /
• 2010

The full-length cDNA of the porcine peroxisomal ${\Delta}^3$,${\Delta}^2$-enoyl-CoA isomerase (PECI) gene encodes a monofunctional peroxisomal ${\Delta}^3$,${\Delta}^2$-enoyl-CoA isomerase. Cloning and sequencing of the porcine PECI cDNA revealed the presence of an 1185-base pair open reading frame predicted to encode a 394-amino acid protein by the 5'rapid amplification of cDNA ends (5'RACE) and EST sequences. The porcine PECI gene was expressed in seven tissues (heart, liver, spleen, lung, kidney, skeletal muscle, fat) which was revealed by reverse transcriptase-polymerase chain reaction (RT-PCR). The porcine PECI was mapped to SSC71/2 p11-13 using the somatic cell hybrid panel (SCHP) and the radiation hybrid panel (RH) (LOD score 12.84). The data showed that PECI was closely linked to marker S0383. A C/T single nucleotide polymorphism in PECI exon 10 (3'UTR) was detected as a PvuII PCR-RFLP. Association analysis in our experimental pig population showed that different genotypes of PECI gene were significantly associated with the Average Backfat thickness (ABF) (p<0.05) and Buttock backfat thickness (p<0.01).

• Clinical and Experimental Pediatrics
• /
• v.61 no.12
• /
• pp.403-406
• /
• 2018

Floating-Harbor syndrome is a rare autosomal dominant genetic disorder associated with SRCAP mutation. To date, approximately 50 cases of Floating-Harbor syndrome have been reported, but none have been reported in Korea yet. Floating-Harbor syndrome is characterized by delayed bony maturation, unique facial features, and language impairment. Here, we present a 6-year-old boy with a triangular face, deep-set protruding eyes, low-set ears, wide nose with narrow nasal bridge, short philtrum, long thin lips, clinodactyly, and developmental delay that was transferred to our pediatric clinic for genetic evaluation. He showed progressive delay in the area of language and cognition-adaption as he grew. He had previously undergone chromosomal analysis at another hospital due to his language delay, but his karyotype was normal. We performed targeted exome sequencing, considering several syndromes with similar phenotypes. Library preparation was performed with the TruSight One sequencing panel, which enriches the sample for about 4,800 genes of clinical relevance. Massively parallel sequencing was conducted with NextSeq. An identified variant was confirmed by Sanger sequencing of the patient and his parents. Finally, the patient was confirmed as the first Korean case of Floating-Harbor syndrome with a novel SRCAP (Snf2 related CREBBP activator protein) mutation (c.7732dupT, p.Ser2578Phefs*6), resulting in early termination of the protein; it was not found in either of his healthy parents or a control population. To our knowledge, this is the first study to describe a boy with Floating-Harbor syndrome with a novel SRCAP mutation diagnosed by targeted exome sequencing in Korea.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.9
• /
• pp.4071-4075
• /
• 2015

Background: Retinoblastoma protein-interacting zinc finger gene 1(RIZ1) functions as a tumor suppressor. Hypermethylation-mediated RIZ1 silencing has been reported in several cancers, but not in renal cell carcinoma (RCC) yet. Materials and Methods: We examined the RIZ1 expression and methylation in a panel of RCC cell lines and 50 primary tumors using semiquantitative/quantitative polymerase chain reaction (PCR), methylation specific PCR, and bisulfite sequencing genomic. We also explored the relationship between methylation status of RIZ1 and clinicopathological features in RCC patients. Results: RIZ1 expression was down-regulated or lost in OS-RC-2, 769-P, Caki-1, 786-O and A498 RCC cell lines. Restored expression of RIZ1 was detected after addition of 5-aza-2'-deoxycytidine with/without trichostatin A, suggesting that DNA methylation directly mediates its silencing. The RIZ1 expression was significantly reduced in RCCs compared to adjacent non-malignant renal samples (P<0.001). Aberrant methylation was detected in 15 of 50 (30%) RCCs and in 2 of 28 (7%) adjacent non-malignant renal samples (P=0.02). No statistically significant correlation between methylated and unmethylated cases with regard to age, gender, pathological stage and grade was observed. Conclusions: RIZ1 expression is down-regulated in human RCC, and this down-regulation is associated with methylation. RIZ1 methylation may play a role in renal carcinogenesis.

• Asian-Australasian Journal of Animal Sciences
• /
• v.21 no.7
• /
• pp.917-922
• /
• 2008

A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif (ADAMTS1) plays a critical role in follicular rupture and represents a major advance in the proteolytic events that control ovulation. In this study, a 9,026-bp DNA sequence containing the full coding region, all 8 introns and part of the 5'and 3' untranslated region of the porcine ADAMTS1 gene was obtained. Analysis of the ADAMTS1 gene using the porcine radiation hybrid panel indicated that pig ADAMTS1 is closely linkage with microsatellite marker S0215, located on SSC13q49. The open reading frame of its cDNA covered 2,844 bp and encoded 947 amino acids. The coding region of porcine ADAMTS1 as determined by sequence alignments shared 85% and 81% identity with human and mouse cDNAs, respectively. The deduced protein contained 947 amino acids showing 85% sequence similarity both to the human and mouse proteins, respectively. Comparative sequencing of three pig breeds revealed one single nucleotide polymorphism (SNP) within exon 7 of which a G-C substitution at position 6006 changes a codon for arginine into a codon for proline. The substitution was situated within a PvuII recognition site and developed as a PCR-RFLP marker for further use in population variation investigations and association analysis with litter size. Allele frequencies of this SNP were investigated in seven pig breeds/lines. An association analysis in a new Qingping female line suggested that different ADAMTS1 genotypes have significant differences in litter size (p<0.01).