• Genomics & Informatics
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• 제19권4호
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• pp.40.1-40.11
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• 2021

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.

• Clinical and Experimental Pediatrics
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• 제57권1호
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• pp.46-49
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• 2014

CHARGE syndrome has been estimated to occur in 1:10,000 births worldwide and shows various clinical manifestations. It is a genetic disorder characterized by a specific and a recognizable pattern of anomalies. The major clinical features are ocular coloboma, heart malformations, atresia of the choanae, growth retardation, genital hypoplasia, and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene, located on chromosome 8q12.1, causes CHARGE syndrome. The CHD7 protein is an adenosine triphosphate (ATP)-dependent chromatin remodeling protein. A total of 67% of patients clinically diagnosed with CHARGE syndrome have CHD7 mutations. Five hundred twenty-eight pathogenic and unique CHD7 alterations have been identified so far. We describe a patient with a CHARGE syndrome diagnosis who carried a novel de novo mutation, a c.3896T>C (p. leu1299Pro) missense mutation, in the CHD7 gene. This finding will provide more information for genetic counseling and expand our understanding of the pathogenesis and development of CHARGE syndrome.

• Journal of Genetic Medicine
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• 제17권2호
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• pp.92-96
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• 2020

Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS) is an autosomal-dominant, extremely rare neurodevelopmental disorder caused by the heterozygous EBF3 gene mutation. EBF3 is located on chromosome 10q26.3 and acts as a transcription factor that regulates neurogenesis and differentiation. This syndrome is characterized by dysmorphism, cerebellar hypoplasia, urogenital anomaly, hypotonia, ataxia, intellectual deficit, and speech delay. The current report describes a 3-year-old Korean male carrying a de novo EBF3 mutation, c.589A>G (p.Asn197Asp), which was identified by whole exome sequencing. He manifested facial dysmorphism, hypotonia, strabismus, vermis hypoplasia, and urogenital anomalies, including vesicoureteral reflux, cryptorchidism, and areflexic bladder. This is the first report of a case of HADDS cause by an EBF3 mutation in the Korean population.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.4095-4101
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• 2015

IDH1/2 mutations which result in alternation in DNA methylation pattern are one of the most common methylation associated mutations in Acute myeloid leukaemia. IDH1/2 mutations frequently associated with higher platelet level, normal cytogentics and NPM1 mutations. Here we analyzed IDH1/2 mutations in 200 newly diagnosed unselected Indian adult AML patients and investigated their correlation with clinical, cytogenetic parameters along with cooperating NPM1 mutation. We detected 5.5% and 4% mutations in IDH1/2 genes, respectively. Except IDH2 c.515_516GG>AA mutation, all the other identified mutations were reported mutations. Similar to reported c.515G>A mutation, the novel c.515_516GG>AA mutation replaces $172^{nd}$ arginine to lysine in the active site of the enzyme. Even though there was a preponderance of IDH1/2 mutations in NK-AML, cytogenetically abnormal patients also harboured IDH1/2 mutations. IDH1 mutations showed significant higher platelet count and NPM1 mutations. IDH2 mutated patients displayed infrequent NPM1 mutations and lower WBC count. All the NPM1 mutations in the IDH1/2 mutated cases showed type A mutation. The present data suggest that IDH1/2 mutations are associated with normal cytogenetics and type A NPM1 mutations in adult Indian AML patients.

• Journal of Genetic Medicine
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• 제16권2호
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• pp.71-75
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• 2019

Periventricular nodular heterotopia (PNH) is a malformation of cortical development in which normal neurons inappropriately cluster in periventricular areas. Patients with Mowat-Wilson syndrome (MWS) typically present with facial gestalt, complex neurologic problems (e.g., severe developmental delay with marked speech impairment and epilepsy), and multiple anomalies (e.g., Hirschsprung disease, urogenital anomalies, congenital heart defects, eye anomalies, and agenesis of the corpus callosum [CC]). MWS is mostly caused by haploinsufficiency of the gene encoding zinc-finger E-box-binding homeobox 2 (ZEB2) due to premature stops or large deletions. We present a case report of a 9-year-old girl with PNH, drug-responsive epilepsy, severe intellectual disability, and facial dysmorphisms only in whom we performed whole-exome sequencing and found a de novo heterozygous missense mutation (c.3134A>C; p.His1045Pro) of ZEB2 (NM_014795.3; NP_055610.1). This mild case of MWS caused by a rare novel missense mutation of ZEB2 represents the first report of MWS with isolated PNH.

• Genes and Genomics
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• 제40권12호
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• pp.1269-1277
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• 2018

Bcl2-associated athanogene 3 (BAG3) mutations have been reported to cause the myofibrillar myopathy (MFM) which shows progressive limb muscle weakness, respiratory failure, and cardiomyopathy. Myopathy patients with BAG3 mutation are very rare. We described a patient showing atypical phenotypes. We aimed to find the genetic cause of Korean patients with sensory motor polyneuropathy, myopathy and rigid spine. We performed whole exome sequencing (WES) with 423 patients with sensory motor polyneuropathy. We found BAG3 mutation in one patient with neuropathy, myopathy and rigid spine syndrome, and performed electrophysiological study, whole body MRI and muscle biopsy on the patient. A de novo heterozygous p.Pro209Leu (c.626C>T) mutation in BAG3 was identified in a female myopathy. She first noticed a gait disturbance and spinal rigidity at the age of 11, and serum creatine kinase levels were elevated ninefolds than normal. She showed an axonal sensory-motor polyneuropathy like Charcot-Marie-Tooth disease (CMT), myopathy, rigid spine and respiratory dysfunction; however, she did not show any cardiomyopathy, which is a common symptom in BAG3 mutation. Lower limb MRI and whole spine MRI showed bilateral symmetric fatty atrophy of muscles at the lower limb and paraspinal muscles. When we track traceable MRI 1 year later, the muscle damage progressed slowly. As far as our knowledge, this is the first Korean patient with BAG3 mutation. We described a BAG3 mutation patient with atypical phenotype of CMT and myopathy, and those are expected to broaden the clinical spectrum of the disease and help to diagnose it.

• Clinical and Experimental Pediatrics
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• 제50권10호
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• pp.1024-1029
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• 2007

Costello 증후군은 특징적 얼굴 형태(coarse face), 발달 장애, 지능 저하, 성장 지연, 신경학적 이상, 심근증, 피부 병변, 수유 장애, 상대적 대두증, 소관절의 과신전, 고형종 발생 증가 등을 특징으로 하는 드문 증후군으로 1977년 Costello에 의해 처음으로 보고되었으며, 이후 전세계적으로 약 100례 이상이 보고되었다. 최근 Costello 증후군은 HRAS 유전자 내의 glycine 12 또는 13 codon을 침범하는 de novo mutation에 의해 발생하는 것으로 알려져 있다. 저자들은 특징적인 얼굴 형태와 지능 저하, 대두증, 손과 발의 과도한 주름, 비후성 심근증과 심방성 빈맥으로 특징지어지는 Costello 증후군으로 진단된 환아 3례를 경험하였기에 이를 보고하는 바이다.

• Clinical and Experimental Pediatrics
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• 제62권5호
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• pp.193-197
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• 2019

Alport syndrome (ATS) is an inherited glomerular disease caused by mutations in one of the type IV collagen novel chains (${\alpha}3$, ${\alpha}4$, and ${\alpha}5$). ATS is characterized by persistent microscopic hematuria that starts during infancy, eventually leading to either progressive nephritis or end-stage renal disease. There are 3 known genetic forms of ATS, namely X-linked ATS, autosomal recessive ATS, and autosomal dominant ATS. About 80% of patients with ATS have X-linked ATS, which is caused by mutations in the type IV collagen ${\alpha}5$ chain gene, COL4A5. Although an 80% mutation detection rate is observed in men with X-linked ATS, some difficulties do exist in the genetic diagnosis of ATS. Most mutations are point mutations without hotspots in the COL4A3, COL4A4, and COL4A5 genes. Further, there are insufficient data on the detection of COL4A3 and COL4A4 mutations for their comparison between patients with autosomal recessive or dominant ATS. Therefore, diagnosis of ATS in female patients with no apparent family history can be challenging. Therefore, in this study, we used whole-exome sequencing (WES) to identify mutations in type IV collagen in 2 girls with glomerular basement membrane structural changes suspected to be associated with ATS; these patients had no relevant family history. Our results revealed de novo c.4688G>A (p.Arg1563Gln) and c.2714G>A (p.Gly905Asp) mutations in COL4A5. Therefore, we suggest that WES is an effective approach to obtain genetic information in ATS, particularly in female patients without a relevant family history, to detect unexpected DNA variations.

• Clinical and Experimental Pediatrics
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• 제59권sup1호
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• pp.29-31
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• 2016

Glucose transport 1 (GLUT-1) deficiency is a rare syndrome caused by mutations in the glucose transporter 1 gene (SLC2A1) and is characterized by early-onset intractable epilepsy, delayed development, and movement disorder. De novo mutations and several hot spots in N34, G91, R126, R153, and R333 of exons 2, 3, 4, and 8 of SLC2A1 are associated with this condition. Seizures, one of the main clinical features of GLUT-1 deficiency, usually develop during infancy. Most patients experience brief and subtle myoclonic jerk and focal seizures that evolve into a mixture of different types of seizures, such as generalized tonic-clonic, absence, myoclonic, and complex partial seizures. Here, we describe the case of a patient with GLUT-1 deficiency who developed infantile spasms and showed delayed development at 6 months of age. She had intractable epilepsy despite receiving aggressive antiepileptic drug therapy, and underwent a metabolic workup. Cerebrospinal fluid (CSF) examination showed CSF-glucose-to-blood-glucose ratio of 0.38, with a normal lactate level. Bidirectional sequencing of SLC2A1 identified a missense mutation (c.1198C>T) at codon 400 (p.Arg400Cys) of exon 9.

• BMB Reports
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• 제51권1호
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• pp.1-2
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• 2018

Positive selection on a new beneficial mutation generates a characteristic pattern of DNA sequence polymorphism when it reaches an intermediate allele frequency. On genome sequences of African Drosophila melanogaster, we detected such signatures of selection at 37 candidate loci and identified "sweeping haplotypes (SHs)" that are increasing or have increased rapidly in frequency due to hitchhiking. Based on geographic distribution of SH frequencies, we could infer whether selective sweeps occurred starting from de novo beneficial mutants under simple constant selective pressure. Single SHs were identified at more than half of loci. However, at many other loci, we observed multiple independent SHs, implying soft selective sweeps due to a high beneficial mutation rate or parallel evolution across space. Interestingly, SH frequencies were intermediate across multiple populations at about a quarter of the loci despite relatively low migration rates inferred between African populations. This invokes a certain form of frequency-dependent selection such as heterozygote advantage. At one locus, we observed a complex pattern of multiple independent that was compatible with recurrent frequency-dependent positive selection on new variants. In conclusion, genomic patterns of positive selection are very diverse, with equal contributions of hard and soft sweeps and a surprisingly large proportion of frequency-dependent selection in D. melanogaster populations.