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The field of genetic counseling (GC) in the Republic of Korea has evolved from a single medical doctor's clinic to a multidisciplinary service with medical geneticists and non-medical professionals working as a team. Here, we assessed the current status of GC in the Republic of Korea based on professional surveys from the perspective of laboratory physicians. An electronic survey was designed and conducted, with the respondents being 50 certified laboratory physicians who were members of the Korean Society for Genetic Diagnostics. Among the 50 respondents, 12 (24%) operated GC clinics. The number of sessions and cases of GC have been on the rise over the last few years, and counseling for cancer genetics was the most common request. Most respondents considered a good understanding of the genetic test and the ability to interpret the test results as strengths of laboratory physicians as medical geneticists, while the lack of clinical experience was a weakness. Education programs regarding laboratory physicians' needs should be provided for high-quality counseling. Lastly, improving the efficiency of GC by strengthening the workforce through a multidisciplinary team is necessary.
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Introduction: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer commonly used in blood bags. Despite its protective effects on red blood cell (RBC) storage, concerns about its reproductive toxicity exist. This study investigated the in vitro quality of RBC concentrates stored in bags using di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) as an alternative plasticizer. Methods: Using a pool-and-split study design, we produced 20 matched homogenous quintets of RBC concentrates in two DINCH bags and three DEHP bags with citrate phosphate dextrose adenine (CPDA-1) anticoagulant. RBC storage quality was assessed weekly for 35 days. Results: On day 35, the median hemolysis levels in the DINCH bags (0.297-0.342%) were marginally higher (p < 0.05) than the DEHP bags (0.204-0.240%). All DINCH bags showed <0.8% hemolysis. RBCs in the DINCH bags showed increased mean corpuscular volume and decreased eosin 5' maleimide binding than in the DEHP bags. Higher pO2 and lower pCO2 levels in the DINCH bags indicated better gas permeability than in DEHP bags. Other metabolic parameters were comparable in both bags. Compared to DEHP, DINCH exhibited considerably lower levels of plasticizer leaching into blood bags. Conclusion: The quality of RBC concentrates stored for 35 days in DINCH-plasticized blood bags with CDPA-1 is generally comparable to those in DEHP bags. Hence, DINCH can be a viable alternative to DEHP in blood bags for nonleukoreduced RBC storage even without the use of next-generation additive solutions to improve RBC preservation quality.
A plasticizer is a chemical substance added to plastic to increase its flexibility. DEHP is a plasticizer that has been widely used in many products including plastic tubing and bags of medical devices. However, concerns about DEHP-related toxicity have been debated for many years. DEHP has been replaced with other plasticizers in many products, but it is still being used in blood bags due to its protective effect on RBC preservation. DINCH is an alternative plasticizer with a low toxicology profile. This study investigated the quality of RBC concentrates stored in blood bags using DINCH. Twenty sets of five RBC concentrates were produced using two DINCH bags and three DEHP bags with CPDA-1 anticoagulant, and the storage quality was assessed weekly for 35 days. On day 35, the median hemolysis levels in the DINCH bags (0.2970.342%) were slightly increased than the DEHP bags (0.2040.240%). However, all DINCH bags showed hemolysis lower than the regulatory limit of 0.8%. DINCH bags exhibited better gas permeability than DEHP bags. Compared to DEHP, DINCH exhibited considerably lower levels of plasticizer leaching into blood bags. Most of the other metabolic parameters were comparable in both bags. The quality of nonleukocyte-reduced RBC concentrates stored for 35 days in DINCH-plasticized blood bags with CDPA-1 is generally comparable to those in DEHP bags. Hence, DINCH can be a viable alternative to DEHP in blood bags for RBC storage, even without the use of next-generation additive solutions to improve RBC preservation quality.
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AIMS: Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB. METHODS: From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored. RESULTS: A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4 years. The mean drug clearance and exposure were 13.6 L/h and 57.9 mg h/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure. CONCLUSION: SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.
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Tuberculosis Pulmonar , Tuberculosis , Femenino , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Rifampin , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/genéticaRESUMEN
BACKGROUND: SNCA multiplication is a genomic cause of familial PD, showing dosage-dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. OBJECTIVES: We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole-genome sequencing data to elucidate the mechanism of SNCA duplication. METHODS: Six patient samples with SNCA duplication underwent whole-genome sequencing. The duplicated regions were defined with nucleotide-resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non-B DNA-forming sequences and stem-loop structure predictions was conducted. RESULTS: Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2-4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem-loop structures. CONCLUSION: Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem-loop structures suggest that replication-based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society.
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Duplicación de Gen , Reordenamiento Génico , Enfermedad de Parkinson , alfa-Sinucleína/genética , Humanos , Enfermedad de Parkinson/genéticaRESUMEN
Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.
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Adenosina Trifosfatasas/genética , Elementos Alu/genética , Proteínas de Transporte de Catión/genética , Variaciones en el Número de Copia de ADN/genética , Paraplejía Espástica Hereditaria/genética , Secuencia de Bases , Línea Celular Transformada , Genotipo , Humanos , Isoformas de Proteínas/genética , Proteínas Recombinantes de Fusión/genética , Análisis de Secuencia de ADN , Eliminación de Secuencia , EspastinaRESUMEN
INTRODUCTION: Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked recessive muscle diseases caused by mutations in the large and complex dystrophin gene. METHODS: We analyzed the dystrophin gene in 507 Korean DMD/BMD patients by multiple ligation-dependent probe amplification and direct sequencing. RESULTS: Overall, 117 different deletions, 48 duplications, and 90 pathogenic sequence variations, including 30 novel variations, were identified. Deletions and duplications accounted for 65.4% and 13.3% of Korean dystrophinopathy, respectively, suggesting that the incidence of large rearrangements in dystrophin is similar among different ethnic groups. We also detected sequence variations in >100 probands. The small variations were dispersed across the whole gene, and 12.3% were nonsense mutations. CONCLUSIONS: Precise genetic characterization in patients with DMD/BMD is timely and important for implementing nationwide registration systems and future molecular therapeutic trials in Korea and globally. Muscle Nerve 55: 727-734, 2017.
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Distrofina/genética , Distrofia Muscular de Duchenne/genética , Mutación , Adolescente , Adulto , Alelos , Niño , Preescolar , Exones , Humanos , Masculino , Polimorfismo Genético , República de Corea , Eliminación de Secuencia , Adulto JovenRESUMEN
Approximately 10% of individuals do not respond to hepatitis B virus (HBV) vaccination, i.e. non-responders (NRs). We aimed to investigate the association of interleukin (IL)-4 and IL-12B gene polymorphisms with responsiveness to the HBV vaccine in Korean infants. Among 300 healthy infants (9-12 month), SNPs for the IL-4 gene (rs2243250, rs2070874, and rs2227284) and for the IL-12B gene (rs3213094 and rs17860508) were compared between subgroups in terms of the response to HBV vaccination. The percentages of NRs (< 10 mIU/mL), low-titer responders (LRs, 10-100 mIU/mL), and high-titer responders (HRs, ≥ 100 mIU/mL) were 20.3%, 37.7% and 42.0%, respectively. No SNPs differed in frequency between NRs and responders or between LRs and HRs. We divided the subjects into two groups according to the time interval from the 3rd dose of HBV vaccination to Ab quantification: > 6 months from the 3rd dose (n = 87) and ≤ 6 months from the 3rd dose (n = 213). In the ≤ 6 month subjects, rs2243250C and rs2227284G were significantly frequent in the lower-titer individuals (NRs + LR) than HRs (40.1 vs. 25.9%, p = 0.014 and 45.1 vs. 33.0%, p = 0.018, respectively), and the rs2243250C and rs2227284G frequencies were significantly different among the three subgroups (13.2 vs. 26.9 vs. 25.9%, p = 0.040 and 15.5 vs. 29.6 vs. 33.0%, p = 0.038, respectively). In conclusion, those results suggest that IL-4 gene polymorphisms may play a role in the response to the HBV vaccine in Korean infants.
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Vacunas contra Hepatitis B/administración & dosificación , Hepatitis B/prevención & control , Subunidad p40 de la Interleucina-12/genética , Interleucina-4/genética , Polimorfismo de Nucleótido Simple , Biomarcadores/sangre , Femenino , Frecuencia de los Genes , Genotipo , Anticuerpos Antihepatitis/sangre , Hepatitis B/genética , Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Humanos , Esquemas de Inmunización , Lactante , Masculino , Farmacogenética , Fenotipo , República de Corea , Factores de Tiempo , Resultado del Tratamiento , VacunaciónRESUMEN
PURPOSE: Although many hypotheses regarding the pathogenesis of polycystic ovary syndrome (PCOS) have been generated, genetic studies have not identified specific genes that play a role in PCOS etiopathogenesis. This study aimed to investigate the relationship between TGF-ß1 gene polymorphism and PCOS in Koreans. METHOD: A total of 51 Korean women with PCOS and 69 healthy women were enrolled. We analyzed 4 single nucleotide polymorphisms (SNPs) of the TGF-ß1 gene (rs11466313, rs1800469, rs2317130, and rs4803457). We also analyzed laboratory measurements, such as free testosterone, glucose, and cholesterol. RESULTS: The frequencies of rs1800469T allele negativity, rs4803457T allele negativity, the rs1800469CC genotype, and the rs4803457CC genotype showed positive associations with PCOS (P = 0.003, P = 0.027, P = 0.009, and P=0.031, respectively), whereas the haplotypes rs1800469C-rs4803457T and rs1800469T-rs4803457T showed negative associations with PCOS. A strong protective effect of the "rs1800469CT-rs4803457TT" combination (OR = 0.09) and a strong risk effect of "rs1800469CC-rs4803457CC" (OR = 6.23) for PCOS were observed. The rs1800469C/T and rs2317130C/T SNPs exhibited associations with several laboratory measurements with various levels of significance. CONCLUSION: The results demonstrated an association of TGF-ß1 gene polymorphisms with the development and/or characteristics of PCOS in the Korean population.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Síndrome del Ovario Poliquístico/genética , Factor de Crecimiento Transformador beta1/genética , Adulto , Alelos , Femenino , Genotipo , Haplotipos , Humanos , Síndrome del Ovario Poliquístico/patología , Polimorfismo de Nucleótido Simple , República de CoreaRESUMEN
We evaluated the diagnostic and clinical usefulness of blood specimens to detect Middle East respiratory syndrome coronavirus infection in 21 patients from the 2015 outbreak in South Korea. Viral RNA was detected in blood from 33% of patients at initial diagnosis, and the detection preceded a worse clinical course.
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Infecciones por Coronavirus/sangre , Coronavirus del Síndrome Respiratorio de Oriente Medio , ARN Viral/sangre , Adulto , Anciano , Anciano de 80 o más Años , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Brotes de Enfermedades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Evaluación del Resultado de la Atención al Paciente , Pronóstico , República de Corea/epidemiología , Adulto JovenRESUMEN
During the 2015 Middle East respiratory syndrome coronavirus outbreak in South Korea, we sequenced full viral genomes of strains isolated from 4 patients early and late during infection. Patients represented at least 4 generations of transmission. We found no evidence of changes in the evolutionary rate and no reason to suspect adaptive changes in viral proteins.
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Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Brotes de Enfermedades , Evolución Molecular , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Adulto , Infecciones por Coronavirus/historia , Infecciones por Coronavirus/transmisión , Variación Genética , Genoma Viral , Historia del Siglo XXI , Humanos , Masculino , Coronavirus del Síndrome Respiratorio de Oriente Medio/aislamiento & purificación , República de Corea/epidemiologíaRESUMEN
BACKGROUND: von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients. METHODS: Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated. RESULTS: We identified 10 different VHL mutations. The c.160_161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; ß domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05). CONCLUSIONS: This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma.
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Estudios de Asociación Genética , Hemangioblastoma/etiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/complicaciones , Enfermedad de von Hippel-Lindau/genética , Adolescente , Adulto , Sitios de Unión/genética , Encéfalo/diagnóstico por imagen , Niño , Femenino , Genotipo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Fenotipo , Polimorfismo Genético , Unión Proteica , República de Corea , Riesgo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/química , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Adulto Joven , Enfermedad de von Hippel-Lindau/patologíaRESUMEN
BACKGROUND: Quantifying the BCR-ABL1 rearrangement is important for monitoring chronic myelogenous leukemia (CML). To standardize BCR-ABL1 quantification, the World Health Organization (WHO) established the first international genetic reference panel. Here, we compared the BCR-ABL1 levels determined using international scale (IS)-based commercially available assays. METHODS: BCR-ABL1 transcripts were quantified using two IS-based assays. 10-1, 10-2, 10-3, 10-4, 10-5 and 10-6 dilutions of the b3a2 positive RNA were used for evaluating linearity, precision, and limit of detection. Correlation of the assay was evaluated by using DNA obtained from CML patients carrying the BCR-ABL1 b3a2 and b2a2 types. RESULTS: Both Ipsogen and Asuragen assays showed fine linearity with reasonable %CV. LOD of each assay was calculated as 0.003% for Ipsogen, and 0.005% for Asuragen. By comparing the results that were lower than 10% by either one of the assay, Ipsogen and Asuragen results showed an overall good linear correlation with a tendency for the Ipsogen assay to show slightly higher levels than the Asuragen assay for b3a2 transcript. For b2a2, the tendency was opposite, with Asuragen showing higher values than the Ipsogen. CONCLUSIONS: Two commercially available IS-based BCR-ABL1 assays showed an overall good quantitative correlation. It should be taken into consideration that each assay tended to produce higher values than the other, depending on the BCR-ABL1 subtypes, suggesting that a separate conversion factor for each subtype can be more helpful when BCR-ABL1 transcript levels are converted into IS.
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Bioensayo/normas , Proteínas de Fusión bcr-abl/genética , Pruebas Genéticas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Estándares de Referencia , Bioensayo/métodos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la EnfermedadRESUMEN
Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.
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Colágeno Tipo II/genética , Artropatías/congénito , Osteocondrodisplasias/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Niño , Exoma , Femenino , Humanos , Artropatías/diagnóstico por imagen , Artropatías/genética , Masculino , Osteocondrodisplasias/diagnóstico por imagen , Linaje , Radiografía , Análisis de Secuencia de ADN/métodosRESUMEN
BACKGROUND: CC-chemokine ligand 28 (CCL28) was previously identified as a novel growth factor in vitro for hematopoietic stem cells (HSCs) from cord blood (CB). However, there is no report on the relationship between CCL28 and HSCs in a human body. STUDY DESIGN AND METHODS: To reveal the effect of CCL28 on hematopoietic cells in human CB at birth, we measured CCL28 in frozen CB plasma, which was preserved as a reference sample for cryopreserved CB units for HSC transplantation. We also evaluated the correlation of CCL28 level with CB components. RESULTS: A total of 81 cryopreserved nonconforming CB units for transplantation were selected. The level of CCL28 was 2540 ± 377 pg/mL. The CCL28 levels correlated with the number of CD34+ cells (r = 0.222, p = 0.047) and white blood cells (r = 0.254, p = 0.022) in the CB units. The CCL28 levels also correlated with hemoglobin levels (r = 0.221, p = 0.048) in fresh CB. CONCLUSION: This finding of positive correlation between CCL28 level and CD34+ cell numbers in vivo, together with the previous report that CCL28 influences the proliferation of hematopoietic cells in CB in vitro, may give a clue for better understanding the variability in HSC content in CB that is cryopreserved for HSC transplantation.
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Quimiocinas CC/sangre , Sangre Fetal/metabolismo , Células Madre Hematopoyéticas/metabolismo , Antígenos CD34/metabolismo , Proliferación Celular/fisiología , Criopreservación , Ensayo de Inmunoadsorción Enzimática , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , HumanosRESUMEN
INTRODUCTION: Erythrocytosis is attributed to various clinical and molecular factors. Many cases of JAK2-unmutated erythrocytosis remain undiagnosed. We investigated the characteristics and causes of JAK2-unmutated erythrocytosis. METHODS: We assessed the clinical and laboratory results of patients with erythrocytosis without JAK2 mutations and performed targeted next-generation sequencing (NGS) panels for somatic and germline mutations. RESULTS: In total, 117 patients with JAK2-unmutated erythrocytosis were included. The median hemoglobin and hematocrit levels were 17.9 g/dL and 53.4%, respectively. Erythropoietin levels were not below the reference range. Thrombotic events were reported in 17 patients (14.5%). Among JAK2-unmutated patients, 44 had undergone targeted panel sequencing consisting of myeloid neoplasm-related genes, and 16 had one or more reportable variants in ASXL1 (5/44), TET2, CALR, FLT3, and SH2B3 (2/44). Additional testing for germline causes revealed eight variants in seven genes in eight patients, including NF1, BPGM, EPAS1, PIEZO1, RHAG, SH2B3, and VHL genes. One NF1 pathogenic, one BPGM likely pathogenic, and six variants of undetermined significance were detected. CONCLUSION: Somatic and germline mutations were identified in 36.4% and 33.3 % of the JAK2-unmutated group; most variants had unknown clinical significance. Not all genetic causes have been identified; comprehensive diagnostic approaches are crucial for identifying the cause of erythrocytosis.
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Secuenciación de Nucleótidos de Alto Rendimiento , Janus Quinasa 2 , Mutación , Policitemia , Humanos , Policitemia/genética , Policitemia/diagnóstico , Janus Quinasa 2/genética , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Mutación de Línea Germinal , Centros de Atención Terciaria , Adulto Joven , Anciano de 80 o más Años , Adolescente , Predisposición Genética a la EnfermedadRESUMEN
The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.
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Diabetes Mellitus Tipo 2 , Masculino , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Pruebas Genéticas , Mutación , República de CoreaRESUMEN
PURPOSE: Universal screening for Lynch syndrome (LS) refers to routine tumor testing for microsatellite instability (MSI) among all patients with colorectal cancer (CRC). Despite its widespread adoption, real-world data on the yield is lacking in Korean population. We studied the yield of adopting universal screening for LS in comparison with pedigree-based screening in a tertiary center. MATERIALS AND METHODS: CRC patients from 2007-2018 were reviewed. Family histories were obtained and were evaluated for hereditary nonpolyposis colorectal cancer (HNPCC) using Amsterdam II criteria. Tumor testing for MSI began in 2007 and genetic testing was offered using all available clinicopathologic data. Yield of genetic testing for LS was compared for each approach and step. RESULTS: Of the 5,520 patients, tumor testing was performed in 4,701 patients (85.2%) and family histories were obtained from 4,241 patients (76.8%). Hereditary CRC (LS or HNPCC) was present in 69 patients (1.3%). MSI-high was present in 6.9%, and 25 patients had confirmed LS. Genetic testing was performed in 41.2% (47/114) of MSI-high patients, out of which 40.4% (19/47) were diagnosed with LS. There were six additional LS patients found outside of tumor testing. For pedigree-based screening, Amsterdam II criteria diagnosed 55 patients with HNPCC. Fifteen of these patients underwent genetic testing, and 11 (73.3%) were diagnosed with LS. Two patients without prior family history were diagnosed with LS and relied solely on tumor testing results. CONCLUSION: Despite widespread adoption of routine tumor testing for MSI, this is not a fail-safe approach to screen all LS patients. Obtaining a thorough family history in combination with universal screening provides a more comprehensive 'universal' screening method for LS.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Linaje , Centros de Atención Terciaria , Reparación de la Incompatibilidad de ADN , Pruebas Genéticas/métodos , Tamizaje Masivo , Inestabilidad de MicrosatélitesRESUMEN
PURPOSE: Combined analysis of the variant composition of circulating tumor DNA (ctDNA) from cell-free plasma and DNA from tumor tissue could provide insight into the implications of the genetic alterations responsible for the intratumoral and intertumoral heterogeneity of gastric cancer. We aimed to evaluate the usefulness of this approach in these patients. METHODS: Cell-free plasma and formalin-fixed paraffin-embedded tumor tissue samples from 46 patients with gastric cancer were examined. Targeted deep sequencing was performed using a commercially available kit. RESULTS: The cell-free DNA (cfDNA) concentration was higher in stage II-IV versus stage I patients and in larger versus smaller tumors. Only 12 of the 36 (33.3%) alterations in the tumor tissue samples were in concordance with those in the ctDNA samples. Two variants were in concordance in stage I samples and 10 in stage II-IV samples. Actionable variants that were detected in concordance were in the stage II-IV samples. Preoperative ctDNA positivity of actionable variants was significantly associated with cfDNA concentration, lymphatic invasion, N stage, and TNM stage. Cancer recurrence was significantly associated with tumor size, lymphatic/vascular invasion, TNM stage, and ctDNA-tumor tissue variant concordance. CONCLUSION: Preoperative ctDNA genetic analysis using a multigene panel offers substantial clinical benefits when performed in conjunction with targeted deep sequencing of tumor tissue. Concordance between preoperative ctDNA and tumor tissue mutations may serve as a prognostic indicator in patients with gastric cancer.
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OBJECTIVE: To examine the efficacy of MSH6 and PMS2 immunohistochemistry (IHC) as a screening method for Lynch syndrome in endometrial cancer patients. METHODS: Through multidisciplinary discussions, an institutional MSH6 and PMS2 IHC-initiated cascade test (MSH6, PMS2 IHCâmicrosatellite instability [MSI] assayâgermline mismatch repair [MMR] gene sequencing) was developed to screen for Lynch syndrome in endometrial cancer patients. Testing was performed on a consecutive cohort of 218 newly diagnosed endometrial cancer patients who underwent surgery at a tertiary hospital in the Republic of Korea between August 2018 and December 2020. The number of MMR deficiencies (MSH6 or PMS2 loss in IHC) and. RESULTS: of subsequent tests (MSI assay and germline MMR gene sequencing) were examined. RESULTS: MMR deficiency was detected in 52 of the 218 patients (24.0%). Among these 52 patients, 34 (65.0%) underwent MSI testing, of which 31 (91.0%) exhibited high MSI. Of the 31 patients with MSI-high status, 15 (48.0%) underwent germline MMR gene sequencing. Subsequently, Lynch syndrome was diagnosed in five patients (33.0%). CONCLUSION: Lynch syndrome screening using MSH6 and PMS2 IHC-initiated cascade testing is a viable strategy in the management of endometrial cancer. A simplified strategy (MSH6 and PMS2 IHCâgermline MMR gene sequencing) was proposed because most women with MMR deficiencies exhibited high MSI.
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PURPOSE: In this study, polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing was comprehensively analyzed and compared with immunohistochemistry (IHC) for mismatch repair (MMR) protein expression in patients with gastric cancer (GC). MATERIALS AND METHODS: In 5,676 GC cases, PCR-based MSI testing using five microsatellites (BAT-26, BAT-25, D5S346, D2S123, and D17S250) and IHC for MLH1 were performed. Re-evaluation of MSI testing/MLH1 IHC and additional IHC for MSH2, MSH6, and PMS2 were performed in discordant/indeterminate cases. RESULTS: Of the 5,676 cases, microsatellite stable (MSS)/MSI-low and intact MLH1 were observed in 5,082 cases (89.5%), whereas MSI-high (MSI-H) and loss of MLH1 expression were observed in 502 cases (8.8%). We re-evaluated the remaining 92 cases (1.6%) with a discordant/indeterminate status. Re-evaluation showed 1) 37 concordant cases (0.7%) (18 and 19 cases of MSI-H/MMR-deficient (dMMR) and MSS/MMR-proficient (pMMR), respectively), 2) 6 discordant cases (0.1%) (3 cases each of MSI-H/pMMR and MSS/dMMR), 3) 14 MSI indeterminate cases (0.2%) (1 case of dMMR and 13 cases of pMMR), and 4) 35 IHC indeterminate cases (0.6%) (22 and 13 cases of MSI-H and MSS, respectively). Finally, MSI-H or dMMR was observed in 549 cases (9.7%), of which 47 (0.8%) were additionally confirmed as MSI-H or dMMR by re-evaluation. Sensitivity was 99.3% for MSI testing and 95.4% for MMR IHC. CONCLUSIONS: Considering the low incidence of MSI-H or dMMR, discordant/indeterminate results were occasionally identified in GCs, in which case complementary testing is required. These findings could help improve the accuracy of MSI/MMR testing in daily practice.