유전의학융합학술지
- E-ISSN : 2671-6771
- Publisher : 유전의학융합학회
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- E-ISSN2671-6771
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The Growing Potential of Long-Read Sequencing in Identifying Previously Elusive Causative Variants in Patients with Undiagnosed Rare Diseases
ChoiYeonsong(Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea. Korean Genomics Center, UNIST, Ulsan, Korea) ; ChoiDavid Whee-Young(Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea. Korean Genomics Center, UNIST, Ulsan, Korea) ; WonHyeyeon(Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea. Korean Genomics Center, UNIST, Ulsan, Korea) ; LeeSemin(Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea. Korean Genomics Center, UNIST, Ulsan, Korea)
pp.15-20
https://doi.org/10.22742/jig.2024.6.2.15
초록보기
초록
Rare diseases, largely driven by genetic factors, present significant diagnostic challenges due to their complex genomic variations. Traditional short-read sequencing methods, such as whole-exome sequencing and whole-genome sequencing, are widely used to detect genomic alterations in a time- and cost-effective manner. However, some rare conditions are often left undiagnosed due to the technical limitations of current sequencing platforms. To overcome these limitations, long-read sequencing (LRS) technology has been applied to various fields of clinical research including rare diseases. With LRS, researchers are able to accurately characterize complex variants such as structural variations, tandem repeats, transposable elements, and transcript isoforms. This review article explores the current applications of LRS in rare disease research, highlighting its potential in identifying previously elusive causative variants in undiagnosed rare diseases.
Abstract
Rare diseases, largely driven by genetic factors, present significant diagnostic challenges due to their complex genomic variations. Traditional short-read sequencing methods, such as whole-exome sequencing and whole-genome sequencing, are widely used to detect genomic alterations in a time- and cost-effective manner. However, some rare conditions are often left undiagnosed due to the technical limitations of current sequencing platforms. To overcome these limitations, long-read sequencing (LRS) technology has been applied to various fields of clinical research including rare diseases. With LRS, researchers are able to accurately characterize complex variants such as structural variations, tandem repeats, transposable elements, and transcript isoforms. This review article explores the current applications of LRS in rare disease research, highlighting its potential in identifying previously elusive causative variants in undiagnosed rare diseases.
KimHyung-Goo(Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, the State University of New Jersey, NJ 08854, USA) ; LeeSang Hoon(Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, the State University of New Jersey, NJ 08854, USA) ; LaymanLawrence C.(Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA. Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA 30912, USA) ; JangMi-Hyeon(Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, the State University of New Jersey, NJ 08854, USA)
pp.21-24
https://doi.org/10.22742/jig.2024.6.2.21
초록보기
초록
The disease gene for delayed puberty is hypothesized to reside within a 3.7 Mb genomic region on chromosome 9, spanning 9q31.2 to 9q31.3, which contains 20 genes. This region aligns with 9q31.3, where the Kallmann syndrome gene is suspected to be located in a patient with a de novo balanced translocation, t(7;9)(p14.1;q31.3). After analyzing the expression patterns and reported genetic variants of the 20 candidate genes, we propose ACTL7A and ACTL7B as strong candidate genes for Kallmann syndrome. Mutation screening of these genes in Kallmann syndrome patients will be essential to confirm their pathological roles in delayed puberty.
Abstract
The disease gene for delayed puberty is hypothesized to reside within a 3.7 Mb genomic region on chromosome 9, spanning 9q31.2 to 9q31.3, which contains 20 genes. This region aligns with 9q31.3, where the Kallmann syndrome gene is suspected to be located in a patient with a de novo balanced translocation, t(7;9)(p14.1;q31.3). After analyzing the expression patterns and reported genetic variants of the 20 candidate genes, we propose ACTL7A and ACTL7B as strong candidate genes for Kallmann syndrome. Mutation screening of these genes in Kallmann syndrome patients will be essential to confirm their pathological roles in delayed puberty.
ShimYe Jee(Department of Pediatrics, Keimyung University School of Medicine, Keimyung University Dongsan Hospital, Daegu, Korea)
pp.25-32
https://doi.org/10.22742/jig.2024.6.2.25
초록보기
초록
Diamond-Blackfan Anemia (DBA) is a rare congenital bone marrow failure syndrome primarily characterized by erythroblastopenia and macrocytic anemia. This disorder results from mutations in ribosomal protein (RP) genes, which lead to defective ribosomal RNA maturation, nucleolar stress, and impaired erythropoiesis. Mutations in RP genes have been identified, with RPS19 being the most commonly affected gene, accounting for approximately 25% of all cases. Other frequently mutated genes include RPL5, RPL11, and RPS26. These mutations are mostly heterozygous and cause defective ribosome assembly and biogenesis, which activates the p53 pathway, resulting in cell cycle arrest and apoptosis. In addition, non-RP gene mutations, such as those in GATA1, TSR2, or HEATR3, have been linked to DBA-like phenotypes, further complicating the genetic landscape. Congenital malformations, particularly craniofacial anomalies, thumb abnormalities, and cardiac defects, are common in patients with specific RP gene mutations, such as RPL5 and RPL11. Advances in next-generation sequencing have improved the identification of novel mutations; however, approximately 20–25% of DBA cases remain genetically unexplained. In this review, we explore the genetic landscape of DBA and provide insights into the underlying mutations and their contributions to disease pathophysiology.
Abstract
Diamond-Blackfan Anemia (DBA) is a rare congenital bone marrow failure syndrome primarily characterized by erythroblastopenia and macrocytic anemia. This disorder results from mutations in ribosomal protein (RP) genes, which lead to defective ribosomal RNA maturation, nucleolar stress, and impaired erythropoiesis. Mutations in RP genes have been identified, with RPS19 being the most commonly affected gene, accounting for approximately 25% of all cases. Other frequently mutated genes include RPL5, RPL11, and RPS26. These mutations are mostly heterozygous and cause defective ribosome assembly and biogenesis, which activates the p53 pathway, resulting in cell cycle arrest and apoptosis. In addition, non-RP gene mutations, such as those in GATA1, TSR2, or HEATR3, have been linked to DBA-like phenotypes, further complicating the genetic landscape. Congenital malformations, particularly craniofacial anomalies, thumb abnormalities, and cardiac defects, are common in patients with specific RP gene mutations, such as RPL5 and RPL11. Advances in next-generation sequencing have improved the identification of novel mutations; however, approximately 20–25% of DBA cases remain genetically unexplained. In this review, we explore the genetic landscape of DBA and provide insights into the underlying mutations and their contributions to disease pathophysiology.
SeolChang Ahn(GC Genome, Yongin, Korea. GC Labs, Yongin, Korea)
pp.33-36
https://doi.org/10.22742/jig.2024.6.2.33
초록보기
초록
Chromosomal microarray (CMA) can detect genome-wide small copy number abnormalities (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) better than conventional karyotyping and fluorescence in situ hybridization (FISH) for hematologic malignancies. Apart from the limitations in detecting balanced chromosomal rearrangements and low-level malignant clones, CMA has clinical utility in detecting significant recurrent and novel variants with diagnostic, prognostic, and therapeutic evidence. It can successfully complement conventional cytogenetic tests for several hematological malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). An increase in CMA testing for hematologic malignancies is expected to identify novel markers of clinical significance.
Abstract
Chromosomal microarray (CMA) can detect genome-wide small copy number abnormalities (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) better than conventional karyotyping and fluorescence in situ hybridization (FISH) for hematologic malignancies. Apart from the limitations in detecting balanced chromosomal rearrangements and low-level malignant clones, CMA has clinical utility in detecting significant recurrent and novel variants with diagnostic, prognostic, and therapeutic evidence. It can successfully complement conventional cytogenetic tests for several hematological malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). An increase in CMA testing for hematologic malignancies is expected to identify novel markers of clinical significance.
MoonJung-Eun(Department of pediatrics, School of Medicine, Kyungpook National University Chilgok Hospital, Daegu, Korea)
pp.37-41
https://doi.org/10.22742/jig.2024.6.2.37
초록보기
초록
Neonatal diabetes mellitus, or congenital diabetes mellitus, is a rare genetic disorder caused by abnormal β cell function and other causes. The symptoms of hyperglycemia that occur in neonatal diabetes. The symptoms of hyperglycemia that occur in neonatal diabetes may be transient or persistent. The most frequent genetic cause of neonatal diabetes characterized by abnormal β cell function is abnormalities at the 6q24 locus. Another possible cause is mutations in the ABCC8 or KCNJ11 genes, which code for potassium channels in pancreatic β cells. This underscores the importance of rapid genetic diagnosis following neonatal diabetes diagnosis and highlights the critical timing of sulfonylurea use.
Abstract
Neonatal diabetes mellitus, or congenital diabetes mellitus, is a rare genetic disorder caused by abnormal β cell function and other causes. The symptoms of hyperglycemia that occur in neonatal diabetes. The symptoms of hyperglycemia that occur in neonatal diabetes may be transient or persistent. The most frequent genetic cause of neonatal diabetes characterized by abnormal β cell function is abnormalities at the 6q24 locus. Another possible cause is mutations in the ABCC8 or KCNJ11 genes, which code for potassium channels in pancreatic β cells. This underscores the importance of rapid genetic diagnosis following neonatal diabetes diagnosis and highlights the critical timing of sulfonylurea use.
ParkJihyun(Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu 42472, Korea) ; JangKyung Mi(Department of Pediatrics, College of Medicine, Yeungnam University, Daegu 42415, Korea)
pp.42-46
https://doi.org/10.22742/jig.2024.6.2.42
초록보기
초록
Background: The most prominent pathological features of Parkinson's disease (PD) are diminished substantia nigra (SN), which is part of the output component of the basal ganglia, the severe death of dopaminergic neuronal cell and the accumulation of a synuclein (αSYN). However, the mechanism by which αSYN causes toxicity and contributes to neuronal death remains unclear. Methods: The aim of this study was to investigate the effect of αSYN/STAT oligodeoxynucleotide (ODN), which simultaneously suppresses STAT transcription factors and αSYN mRNA expression in an in vitro Parkinson's disease model. Results: Synthetic αSYN/STAT ODN effectively inhibits 1-Methyl-4-phenylpyridinium (MPP+) induced STAT phosphorylation and αSYN expression. αSYN/STAT ODN attenuated MPP+ to mimic PD model in vitro. MPP+ induced the secretion of TNF-α/IL-6, inhibited cell viability and induced apoptosis while these effects could be rescued by αSYN/STAT ODN. Conclusion: Therefore, synthetic αSYN/STAT ODN has substantial therapeutic feasibility for the treatment of neurodegenerative diseases.
Abstract
Background: The most prominent pathological features of Parkinson's disease (PD) are diminished substantia nigra (SN), which is part of the output component of the basal ganglia, the severe death of dopaminergic neuronal cell and the accumulation of a synuclein (αSYN). However, the mechanism by which αSYN causes toxicity and contributes to neuronal death remains unclear. Methods: The aim of this study was to investigate the effect of αSYN/STAT oligodeoxynucleotide (ODN), which simultaneously suppresses STAT transcription factors and αSYN mRNA expression in an in vitro Parkinson's disease model. Results: Synthetic αSYN/STAT ODN effectively inhibits 1-Methyl-4-phenylpyridinium (MPP+) induced STAT phosphorylation and αSYN expression. αSYN/STAT ODN attenuated MPP+ to mimic PD model in vitro. MPP+ induced the secretion of TNF-α/IL-6, inhibited cell viability and induced apoptosis while these effects could be rescued by αSYN/STAT ODN. Conclusion: Therefore, synthetic αSYN/STAT ODN has substantial therapeutic feasibility for the treatment of neurodegenerative diseases.
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