Identification of Two Cases of Ciliopathy-Associated Diabetes and Their Mutation Analysis Using Whole Exome Sequencing

Kim, Min Kyeong,Kwak, Soo Heon,Kang, Shinae,Jung, Hye Seung,Cho, Young Min,Kim, Seong Yeon,Park, Kyong Soo Korean Diabetes Association 2015 Diabetes and Metabolism Journal Vol.39 No.5

<P><B>Background</B></P><P>Alström syndrome and Bardet-Biedl syndrome are autosomal recessively inherited ciliopathies with common characteristics of obesity, diabetes, and blindness. Alström syndrome is caused by a mutation in the <I>ALMS1</I> gene, and Bardet-Biedl syndrome is caused by mutations in <I>BBS1-16</I> genes. Herein we report genetically confirmed cases of Alström syndrome and Bardet-Biedl syndrome in Korea using whole exome sequencing.</P><P><B>Methods</B></P><P>Exome capture was done using SureSelect Human All Exon Kit V4+UTRs (Agilent Technologies). HiSeq2000 system (Illumina) was used for massive parallel sequencing. Sanger sequencing was used for genotype confirmation and familial cosegregation analysis.</P><P><B>Results</B></P><P>A 21-year old Korean woman was clinically diagnosed with Alström syndrome. She had diabetes, blindness, obesity, severe insulin resistance, and hearing loss. Whole exome sequencing revealed a nonsense mutation in exon 10 of <I>ALMS1</I> (c.8776C>T, p.R2926X) and a seven base-pair deletion resulting in frameshift mutation in exon 8 (c.6410_6416del, p.2137_2139del). A 24-year-old Korean man had Bardet-Biedl syndrome with diabetes, blindness, obesity, and a history of polydactyly. Whole exome sequencing revealed a nonsynonymous mutation in exon 11 of the <I>BBS1</I> gene (c.1061A>G, p.E354G) and mutation at the normal splicing recognition site of exon 7 of the <I>BBS1</I> gene (c.519-1G>T).</P><P><B>Conclusion</B></P><P>We found novel compound heterozygous mutations of Alström syndrome and Bardet-Biedl syndrome using whole exome sequencing. The whole exome sequencing successfully identified novel genetic variants of ciliopathy-associated diabetes.</P>

Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma

서수현,김정희,김만진,조성임,김수진,강혜인,신찬수,박성섭,이규은,성문우 대한내분비학회 2020 Endocrinology and metabolism Vol.35 No.4

Background: Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort. Methods: Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAM tools. Results: Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected. Conclusion: Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.

Whole-exome sequencing analysis in a case of primary congenital glaucoma due to the partial uniparental isodisomy

Zavarzadeh, Parisima Ghaffarian,Bonyadi, Morteza,Abedi, Zahra Korea Genome Organization 2022 Genomics & informatics Vol.20 No.3

We described a clinical, laboratory, and genetic presentation of a pathogenic variant of the CYP1B1 gene through a report of a case of primary congenital glaucoma and a trio analysis of this candidate variant in the family with the Sanger sequencing method and eventually completed our study with the secondary/incidental findings. This study reports a rare case of primary congenital glaucoma, an 8-year-old female child with a negative family history of glaucoma and uncontrolled intraocular pressure. This case's whole-exome sequencing data analysis presents a homozygous pathogenic single nucleotide variant in the CYP1B1 gene (NM_000104:exon3:c.G1103A:p.R368H). At the same time, this pathogenic variant was obtained as a heterozygous state in her unaffected father but not her mother. The diagnosis was made based on molecular findings of whole-exome sequencing data analysis. Therefore, the clinical reports and bioinformatics findings supported the relation between the candidate pathogenic variant and the disease. However, it should not be forgotten that primary congenital glaucoma is not peculiar to the CYP1B1 gene. Since the chance of developing autosomal recessive disorders with low allele frequency and unrelated parents is extraordinary in offspring. However, further data analysis of whole-exome sequencing and Sanger sequencing method were applied to obtain the type of mutation and how it was carried to the offspring.

The whole-exome sequencing in three families with atopic dermatitis

( Joon Hyuk Seo ),( Moo Yeol Hyun ),( Won Il Heo ),( Kapsok Li ),( Seong Joon Seo ),( Chang Kwun Hong ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: The prevalence of atopic dermatitis (AD) has increased over a recent 10-year. AD tends to run in families that passed down from generation to generation and commonly starts in childhood. It is as high as 20% in children less than 5 years old. Thus, early discovery and therapy of AD are important. It has emerged the necessity of biomarker for early detection of AD. Objectives: The goal of this study is to find novel gene markers for diagnosis of early-onset atopic dermatitis in Koreans. Methods: Peripheral blood was obtained from three families (6 early-onset AD patients and 6 controls) with autosomal dominant condition. Whole Exome Sequencing (WES) was performed using SureSelect Human All Exon V4+UTR 71 Mb. Variants of atopic dermatitis were filtered step by step to gain the important candidate genes. Results: We have confirmed overlapping genes in common variants of filter 5 in three family. 15 genes were overlapped in filter 5 and two of them reached to filter 7 can be called “rare variant”. Uniquely, COL6A6 gene appeared in all of three family. We also found variants of filaggrin, filaggrin2 and IL4R that is well-known makers of atopic dermatitis. Conclusion: We were able to detect COL6A6 gene by finding overlapping genes in rare and common variants of three family. It may become a novel gene as early-onset AD marker.

Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology

Vilarinho, S.,Choi, M.,Jain, D.,Malhotra, A.,Kulkarni, S.,Pashankar, D.,Phatak, U.,Patel, M.,Bale, A.,Mane, S.,Lifton, R.P.,Mistry, P.K. Elsevier Science Publishers 2014 Journal of hepatology Vol.61 No.5

Background & Aims: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology. Methods: Patient 1 was a 10year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8year-old female with progressive syndromic cholestasis of unknown aetiology since age 3months. Results: Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations. Conclusions: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

차세대 염기서열분석을 이용한 유전성 대사질환의 유전진단

기창석,Chang-Seok Ki 대한유전성대사질환학회 2023 대한유전성대사질환학회지 Vol.23 No.2

Inherited metabolic disorders (IMD) are a group of disorders involving various metabolic pathways. Genetic diagnosis of IMD has been challenging because of extremely heterogeneous nature and extensive laboratory and/or phenotype overlap. Conventional genetic diagnosis was a gene-by-gene approach that needs a priori information on the causative genes that might underlie the IMD. Recent implementation of next-generation sequencing (NGS) technologies has changed the process of genetic diagnosis from a gene-by-gene approach to simultaneous analysis of targeted genes possibly associated with the IMD using gene panels or using whole exome/genome sequencing (WES/WGS) covering entire human genes. Clinical NGS tests can be a cost-effective approach for the rapid diagnosis of IMD with genetic heterogeneity and are becoming standard diagnostic procedures.

Mutations in acral melanoma identified by whole exome sequencing

( Dokyoung Yoon ),( Youngkyoung Lim ),( Dong-youn Lee ) 대한피부과학회 2019 대한피부과학회 학술발표대회집 Vol.71 No.2

Background: There is limited research examining the different aspects of genetic alterations between nail apparatus melanoma (NAM) and non-nail acral melanoma (NNAM) Objectives: To uncover previously unidentified novel mutations for the acral melanoma patients and genomic differences between the NAM and the NNAM Methods: We performed whole-exome sequencing on DNA from 31 saliva samples and 31 tumor tissue samples from Korean AM patients pathologically confirmed at Samsung Medical Center (Seoul, Korea) from September 2016 to March 2019. Mutational profiles were compared between NAMs and NNAMs. Results: Prevalence of the detected well-known pathogenic mutations among the primary melanoma samples were BRAF V600E (16.13%), NRAS (9.68%), and KIT (3.23%). We also identified 53 genes that were repeatedly detected in AMs including BRAF, NRAS, CACMA1E, CDC27, CYP4F2, DDX11, and PCMTD1. 19 genes were predicted to be deleterious in developing melanomas including ANGPTL5, BRAF, CSMD3 and EHMT11 among repeatedly detected genes in AMs. Our results revealed several genes such as CSMD3, EHMT1, and MAGI1 were distinct mutations in the NAM. Conclusion: We identified the mutational landscape, genetic alterations, and differences of genetic backgrounds between NAM and NNAM in the Korean population. Because genetic backgrounds are different for NAM and NNAM, it is necessary to approach each disease in a separate way.

Recent Advances in Autism Spectrum Disorders: Applications of Whole Exome Sequencing Technology

Elif Funda Sener,Halit Canatan,Yusuf Ozkul 대한신경정신의학회 2016 PSYCHIATRY INVESTIGATION Vol.13 No.3

Autism spectrum disorders (ASD) is characterized by three core symptoms with impaired reciprocal social interaction and communication, a pattern of repetitive behavior and/or restricted interests in early childhood. The prevalence is higher in male children than in female children. As a complex neurodevelopmental disorder, the phenotype and severity of autism are extremely heterogeneous with differences from one patient to another. Genetics has a key role in the etiology of autism. Environmental factors are also interacting with the genetic profile and cause abnormal changes in neuronal development, brain growth, and functional connectivity. The term of exome represents less than 1% of the human genome, but contains 85% of known disease-causing variants. Whole-exome sequencing (WES) is an application of the next generation sequencing technology to determine the variations of all coding regions, or exons of known genes. For this reason, WES has been extensively used for clinical studies in the recent years. WES has achieved great success in the past years for identifying Mendelian disease genes. This review evaluates the potential of current findings in ASD for application in next generation sequencing technology, particularly WES. WES and whole-genome sequencing (WGS) approaches may lead to the discovery of underlying genetic factors for ASD and may thereby identify novel therapeutic targets for this disorder.

Energy metabolism and whole-exome sequencing-based analysis of Sasang constitution: a pilot study

김형규,이희탁,소지호,정승훈,서대윤,김종열,김상욱,한진 한국한의학연구원 2017 Integrative Medicine Research Vol.6 No.2

Background: Traditional Korean Sasang constitutional (SC) medicine categorizes individuals into four constitutional types [Tae-eum (TE), So-eum (SE), Tae-yang (TY), or So-yang (SY)] based on biological and physiological characteristics. As these characteristics are closely related to the bioenergetics of the human body, we assessed the correlation between SC type and energy metabolism features. Methods: Forty healthy, young (22.3 ± 1.4 years) males volunteered to participate in this study. Participants answered an SC questionnaire, and their face shape, voice tone, and body shape were assessed using an SC analysis tool. Thirty-one participants (10 TE, 10 SE, 3 TY, and 8 SY) were selected for further analysis. Collected blood samples were subjected to blood composition analysis, mitochondrial function analysis, and whole-exome sequencing. Results: The SY type showed significantly lower total cholesterol and high-density lipoprotein cholesterol levels than the SE type. Cellular and mitochondrial Adenosine triphosphate (ATP) levels were similar across types. All types showed similar basal mitochondrial oxygen consumption rates, whereas the TE type showed a significantly lower ATP-linked oxygen consumption rate than the other types. Whole-exome sequencing identified several genes variants that were exclusively detected in particular SC types, including 19 for SE, seven for SY, 11 for TE, and six for TY. Conclusion: SC type-specific differences in mitochondrial function and gene mutations were detected in a small group of healthy, young Korean males. These results are expected to greatly improve the accurate screening and utilization of SC medicine.

Coffin-Lowry Syndrome - The First Genetically Confirmed Case in Korea Diagnosed by Whole Exome Sequencing

Yoon, Ju Young,Cheon, Chong Kun Interdisciplinary Society of GeneticGenomic Medici 2020 Journal of interdisciplinary genomics Vol.2 No.1

Coffin-Lowry syndrome (CLS) is a genetic disorder characterized by intellectual disability, typical facial features, and skeletal abnormalities. But this syndrome shows highly variable clinical manifestations, and can't be diagnosed with conventional chromosome analysis or comparative genomic hybridization, leading to delayed diagnosis. Here we report an 18-year-old boy with CLS diagnosed by whole exome sequencing. Our patient initially presented with developmental delay, facial dysmorphism at the age of 1. At the age of 18, he developed orthopnea due to mitral regurgitation. At the 22 years of age, he was diagnosed as CLS diagnosed by whole exome sequencing. Our case implies that clinical suspicion is important for early diagnosis, and advanced diagnostic tools such as WES should be considered in suspected cases.