Issues, challenges, and future perspectives of genetic counseling in Republic of Korea: Perspectives of laboratory physicians based on a 2022 survey.

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.

Development and validation of a nomogram to predict pulmonary function and the presence of chronic obstructive pulmonary disease in a Korean population.

BACKGROUND: Early suspicion followed by assessing lung function with spirometry could decrease the underdiagnosis of chronic obstructive pulmonary disease (COPD) in primary care. We aimed to develop a nomogram to predict the FEV1/FVC ratio and the presence of COPD. METHODS: We retrospectively reviewed the data of 4241 adult patients who underwent spirometry between 2013 and 2019. By linear regression analysis, variables associated with FEV1/FVC were identified in the training cohort (n = 2969). Using the variables as predictors, a nomogram was created to predict the FEV1/FVC ratio and validated in the test cohort (n = 1272). RESULTS: Older age (ß coefficient [95% CI], - 0.153 [- 0.183, - 0.122]), male sex (- 1.904 [- 2.749, - 1.056]), current or past smoking history (- 3.324 [- 4.200, - 2.453]), and the presence of dyspnea (- 2.453 [- 3.612, - 1.291]) or overweight (0.894 [0.191, 1.598]) were significantly associated with the FEV1/FVC ratio. In the final testing, the developed nomogram showed a mean absolute error of 8.2% between the predicted and actual FEV1/FVC ratios. The overall performance was best when FEV1/FVC < 70% was used as a diagnostic criterion for COPD; the sensitivity, specificity, and balanced accuracy were 82.3%, 68.6%, and 75.5%, respectively. CONCLUSION: The developed nomogram could be used to identify potential patients at risk of COPD who may need further evaluation, especially in the primary care setting where spirometry is not available.

Epidemiology of Congenital Bleeding Disorders: a Nationwide Population-based Korean Study.

BACKGROUND: Except for data in the Korea Hemophilia Foundation Registry, little is known of the epidemiology of congenital bleeding disorders in Korea. METHODS: Data were obtained from the Korean Health Insurance Review and Assessment Service (HIRA) database. RESULTS: From 2010 to 2015, there were 2,029 patients with congenital bleeding disorders in the Korean HIRA database: 38% (n = 775) of these patients had hemophilia A (HA), 25% (n = 517) had von Willebrand disease (vWD), 7% (n = 132) had hemophilia B (HB), and 25% (n = 513) had less common factor deficiencies. The estimated age-standardized incidence rate (ASR) of HA and HB was 1.78-3.15/100,000 and 0.31-0.51/100,000, respectively. That of vWD was 1.38-1.95/100,000. The estimated ASR of HA showed increase over time though the number of new patients did not increase. Most patients with congenital bleeding disorders were younger than 19 years old (47.8%), and most were registered in Gyeonggi (22.1%) and Seoul (19.2%). CONCLUSION: This is the first nationwide population-based study of congenital bleeding disorders in Korea. This study provides data that will enable more accurate estimations of patients with vWD. This information will help advance the comprehensive care of congenital bleeding disorders. We need to continue to obtain more detailed information on patients to improve the management of these diseases.

Hemoglobin Concentration Reference Interval Revisited: a Nationwide Study from Korea.

BACKGROUND: Anemia is a common cause among the elderly for increased mortality. Hemoglobin concentration can be affected by many factors, but the reference interval defined by the World Health Organization has not been adjusted for the previous half century. METHODS: Through using the dataset generated by the National Health Insurance (NHI) health screening program of Republic of Korea, here we attempt to present a close to actual hemoglobin concentration of the Korean population. Between January 2009 and December 2013, a total of 57,409,872 health screening events were registered in the NHI database. Following the exclusion criteria, 6,759,566 participants were enrolled for analyses. RESULTS: Significant portion of the study population was considered 'anemic', while the mean value (2.5% ~ 97.5%) of hemoglobin concentration from the study was 14.8 (12.5 ~ 16.8) g/dL in men and 12.8 (10.6 ~ 14.7) g/ dL in women. Concordant results of hemoglobin concentration declining with age were observed as previous studies have described, supporting the need for separate, possibly lower cutoff in the elderly. CONCLUSIONS: A considerable portion of the participants being categorized as anemia contests the accuracy of the current lower cutoff for anemia. From a large representative dataset, the need for adjustment to the lower cutoff for anemia is suggested.

Real world epidemiology of myeloproliferative neoplasms: a population based study in Korea 2004-2013.

Myeloproliferative neoplasms (MPNs), with an expected increment in number, impose substantial economic and social burdens. To this end, we conducted a nationwide population-based descriptive epidemiology study. We also investigated medical cost associated with MPNs. Prevalence was the highest for essential thrombocythemia (ET) (range 4.1-9.0 per 100,000), followed by polycythemia vera (PV) (range 2.8-5.4 per 100,000) and primary myelofibrosis (PMF) (range 0.5-0.9 per 100,000). ET incurred the highest cumulative total cost at US$35 million and the most frequent hospital visits, while PMF incurred the highest average cost per person at US$5000. The mean hemoglobin level was 16.9 ± 2.2 g/dL for PV males and 15.5 ± 2.7 g/dL for PV females. Further analyses on hemoglobin levels showed the true positive rate of PV from the significantly elevated hemoglobin group (defined as >18.5 g/dL for men and >16.5 g/dL for women) was 3.01% and that of MPNs was 3.1%. Here, we provide the biggest population-based report on MPN epidemiology that can readily be used as a representative Asian data.

Clinical and Molecular Delineation of a Novel Cys1050Phe Missense Mutation in the ABCC9 Gene in a Korean Patient with Cantú Syndrome.

Cantú syndrome is characterized by congenital hypertrichosis, cardiomegaly, and osteochondrodysplasia and is recognized as a rare syndrome. Although it has previously been reported that the majority of affected individuals have a relatively good prognosis, there are no reports on long-term follow up. Here we report the first case of Cantú syndrome in Korea and the associated changes in overall development with rehabilitation over several months.

Heterogeneous lengths of copy number mutations in human coagulopathy revealed by genome-wide high-density SNP array.

BACKGROUND: The recent advent of genome-wide molecular platforms has facilitated our understanding of the human genome and disease, particularly copy number aberrations. We performed genome-wide single nucleotide polymorphism-array in hereditary coagulopathy to delineate the extent of copy number mutations and to assess its diagnostic utility. DESIGN AND METHODS: The study subjects were 17 patients with hereditary coagulopathy from copy number mutations in coagulation genes detected by multiple ligation-dependent probe amplification. Eleven had hemophilia (7 hemophilia A and 4 hemophilia B) and 6 had thrombophilia (4 protein S deficiency and 2 antithrombin deficiency). Single nucleotide polymorphism-array experiments were performed using Affymetrix Genome-Wide Human SNP arrays 6.0. RESULTS: Copy number mutations were identified by single nucleotide polymorphism-array in 9 patients, which ranged in length from 51 Kb to 6,288 Kb harboring 2 to ~160 genes. Single nucleotide polymorphism-array showed a neutral copy number status in 8 patients including 7 with either a single-exon copy number mutation or duplication mutations of PROS1. CONCLUSIONS: This study revealed unexpectedly heterogeneous lengths of copy number mutations underlying human coagulopathy. Single nucleotide polymorphism-array had limitations in detecting copy number mutations involving a single exon or those of a gene with homologous sequences such as a pseudogene.

Development and diagnostic application/evaluation of pandemic (H1N1) 2009 influenza virus-specific monoclonal antibodies.

We prepared mAb specific to the H1N1 2009 virus (H1N1 2009) to facilitate development of an RDT with enhanced sensitivity and specificity. Among these antibodies, we identified two clones--hybridomas 1H7E1 and 3A3H7-that specifically bound to H1N1 2009 (non-seasonal) and were very suitable for application to a diagnostic kit. The affinity constants (K(a)) of 1H7E1 and 3A3H7 were 1.10 × 10(10) and 2.35 × 10(10), respectively. To identify the antibodies, we performed ELISA and immunoblot analyses and found that 1H7E1 recognized a conformational epitope of HA while 3A3H7 recognized a linear epitope. In clinical evaluations using specimens from 215 patients, a lateral flow rapid testing kit comprising these mAb showed a sensitivity of 81.5% (75/92) and a specificity of 96.7% (119/123). Results using the RDT kit were well correlated with conventional RT-PCR methods as commonly and commercially used. Based on our findings, we believe that use of these mAb with a rapid evaluation kit could serve as a good diagnostic tool for H1N1 2009.

Current Issues, Challenges, and Future Perspectives of Genetic Counseling in Korea.

Genetic testing has become increasingly integrated into all areas of healthcare, and complex genetic testing usage continues to grow; thus, the demand for genetic counseling (GC) is likely to increase. However, it is unclear whether the current clinical GC capacity is sufficient for meeting the existing demand. This review describes the current issues, challenges, and future perspectives of GC in Korea based on a professional survey conducted among laboratory physicians. In view of the growing GC demand in the clinical setting, participants expressed a concern about the lack of support from the national healthcare insurance policy and legal requirements, such as certification, for GC practice. The implementation of genetic testing in the overall healthcare system in Korea is in an early phase. Proper implementation can be achieved through education and training of specialists, collaboration among healthcare personnel, proper regulatory oversight, genomic policies, and public awareness. Understanding the current GC capacity, issues, and challenges is a prerequisite for effective strategic planning by healthcare systems considering the expected growth in the demand for clinical genetic services over the next few decades.

Two Cases of SARS-CoV-2-Positive Mothers and Their Newborns in Korea.

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects pregnant women and their fetuses or newborns. We report two infants born to mothers with coronavirus disease 2019 (COVID-19) in Korea. The first case was a healthy female baby born at 39+3 weeks' gestation from a mother diagnosed with COVID-19. The second case was a female baby born at 38+0 weeks' gestation. The newborn in the second case had symptoms of respiratory distress immediately after birth, and nasal continuous positive airway pressure support was applied for 8 hours. Real-time polymerase chain reaction test results for SARS-CoV-2 using amniotic fluid, neonatal nasopharyngeal and oropharyngeal swabs, blood, urine, stool, and rectal swab were all negative in the 1st and 2nd days of life in both cases. Placental pathology showed acute necrotizing deciduitis and intervillous fibrin deposition with acute intervillositis. Although clinical evidence of vertical transmission was not found in our cases, with the possibility of placental inflammation, close monitoring of SARS-CoV-2 positive mothers and their newborn is required.

Dynamic Chronological Changes in Serum Triglycerides Are Associated With the Time Point for Non-alcoholic Fatty Liver Disease Development in the Nationwide Korean Population Cohort.

Background: We investigated the effects of anthropometric, laboratory, and lifestyle factors on the development of non-alcoholic fatty liver disease (NAFLD) in a nationwide, population-based, 4-year retrospective cohort. Methods: The propensity score-matched study and control groups contained 1,474 subjects who had data in the Korean National Health Insurance Service-National Sample Cohort in 2009, 2011, and 2013. NAFLD was defined using medical records of a diagnosis confirmed by primary clinicians and meeting two previously validated fatty liver prediction models. Chronological changes in anthropometric variables, laboratory results, and lifestyle factors during two periods were compared between patient and control groups in order to find out parameters with consistent dynamics in pre-NAFLD stage which was defined as period just before the NAFLD development. Results: Among the 5 anthropometric, 10 laboratory, and 3 lifestyle factors, prominent chronological decremental changes in serum triglycerides were consistently observed during the pre-NAFLD stage, although the degrees of changes were more predominant in men (-9.46 mg/dL) than women (-5.98 mg/dL). Furthermore, weight and waist circumference changes during the pre-NAFLD stage were noticeable only in women (+0.36 kg and +0.9 cm for weight and waist circumference, respectively), which suggest gender difference in NAFLD. Conclusion: Early screening strategies for people with abrupt chronological changes in serum triglycerides to predict NAFLD development before the progression is recommended.

Evaluation of a rapid diagnostic test, NanoSign® Influenza A/B Antigen, for detection of the 2009 pandemic influenza A/H1N1 viruses.

BACKGROUND: This study evaluated the clinical accuracy and analytical sensitivity of the NanoSign® Influenza A/B antigen kit in detecting 2009 pandemic influenza A/H1N1 viruses. The kit is one of the most popular rapid diagnostic tests for detecting influenza in Republic of Korea. RESULTS: The NanoSign® Influenza A/B kit resulted in 79.4% sensitivity and 97.2% specificity compared to RT-PCR in the detection of the viruses from 1,023 specimens. In addition, the kit was able to detect two strains of novel influenza viruses, Influenza A/California/12/2009(H1N1) and clinically isolated wild-type novel influenza A/H1N1, both of which are spreading epidemically throughout the world. In addition, the correlation between NanoSign® Influenza A/B test and conventional RT-PCR was approximately 94%, indicating a high concordance rate. Analytical sensitivity of the kit was approximately 73 ± 3.65 ng/mL of the purified viral proteins and 1.13 ± 0.11 hemagglutination units for the cultured virus. CONCLUSIONS: As the NanoSign® Influenza A/B kit showed relatively high sensitivity and specificity and the good correlation with RT-PCR, it will be very useful in the early control of influenza infection and in helping physicians in making early treatment decisions.

Genetic Counseling Status and Perspectives Based on a 2018 Professional Survey in Korea.

BACKGROUND: Genetic counseling (GC) provides many benefits, including the identification of patients appropriate for testing, patient education, and medical management. We evaluated the current status of and challenges faced by GC practitioners in Korean hospitals. METHODS: An electronic survey was designed and conducted in 52 certified laboratory physicians belonging to the Korean Society of Laboratory Medicine, from August to September 2018. The questionnaires addressed three main categories of information: (1) current status of GC in hospitals; (2) essential qualifications of GC practitioners; and (3) challenges and perspectives for GC. Fisher's exact test was applied to analyze categorical data. RESULTS: Among a total of 52 participants who initially responded, 12 (23.1%) were performing GC either by direct or indirect care. GC clinics were opened regularly for one (33.3%) or more than three sessions (25.0%) per week; most respondents spent more time for pre-visit activities than in-person visits, both for a initial visit patient and for a follow-up visit patient. All laboratory physicians provided genetic information to their patients. Most recommended family genetic testing when indicated (91.7%), discussed disease management (75.0%), and/or ordered additional genetic testing (58.3%), and some referred patients to other specialists (8.3%). CONCLUSIONS: Both patients and laboratory physicians concede the advantage of GC performed by clinical geneticists; however, the practice of GC involves several challenges and raises some concerns. The cost and support required to implement GC need to be addressed in order to provide qualified GC in Korea.

Oxidative status in iron-deficiency anemia.

Oxidative stress is an imbalance between free radicals and antioxidant molecules that can play an important role in the pathogenesis of iron-deficiency anemia (IDA). The aim of this study was to investigate oxidative status in patients with IDA and alteration of oxidative status after iron treatment. Thirty-three female patients with IDA and 25 healthy controls were included in this study. Oxidant and total antioxidant capacity were determined using free oxygen radicals test and free oxygen radicals defence (Form CR 3000, Callegari, Parma, Italy). Catalase activity was measured by spectrophotometer using a commercially available kit (Bioxytech Catalase-520, OxisResearch, Portland, OR). Oxidant activity in patients with IDA was significantly higher than controls (P<0.05), while total antioxidant and catalase activity were significantly lower (P<0.05). After treatment, oxidant, antioxidant, and catalase activity reached the levels of the control group, and no significant differences were observed among groups (P>0.05). In conclusion, our data indicate that blood reactive oxygen species was lower and total antioxidant and catalase activity were higher after rather than before treatment in patients with IDA. The results of our study support the higher oxidative stress hypothesis in IDA; however, due to the limited number of cases included, more studies may be required to confirm the results.

A novel de novo mutation in the serine-threonine kinase STK11 gene in a Korean patient with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is an unusual autosomal dominant disorder characterized by mucocutaneous pigmentation and multiple gastrointestinal hamartomatous polyps. Patients with PJS are at an increased risk of developing multi-organ cancer, most frequently those involving the gastrointestinal tract. Germline mutation of the STK11 gene, which encodes a serine-threonine kinase, is responsible for PJS. METHODS: Using DNA samples obtained from the patient and his family members, we sequenced nine exons and flanking intron regions of the STK11 gene using polymerase chain reaction (PCR) and direct sequencing. RESULTS: Sequencing of the STK11 gene in the proband of the family revealed a novel 1-base pair deletion of guanine (G) in exon 6 (c.826delG; Gly276AlafsX11). This mutation resulted in a premature termination at codon 286, predicting a partial loss of the kinase domain and complete loss of the C-terminal domain. We did not observe this mutation in both parents of the PJS patient. Therefore, it is considered a novel de novo mutation. CONCLUSION: The results presented herein enlarge the spectrum of mutations of the STK11 gene by identifying a novel de novo mutation in a PJS patient and further support the hypothesis that STK11 mutations are disease-causing mutations for PJS with or without a positive family history.

Clinical Implications of Quantitative JAK2 V617F Analysis using Droplet Digital PCR in Myeloproliferative Neoplasms.

BACKGROUND: JAK2 V617F is the most common mutation in myeloproliferative neoplasms (MPNs) and is a major diagnostic criterion. Mutation quantification is useful for classifying patients with MPN into subgroups and for prognostic prediction. Droplet digital PCR (ddPCR) can provide accurate and reproducible quantitative analysis of DNA. This study was designed to verify the correlation of ddPCR with pyrosequencing results in the diagnosis of MPN and to investigate clinical implications of the mutational burden. METHODS: Peripheral blood or bone marrow samples were obtained from 56 patients newly diagnosed with MPN or previously diagnosed with MPN but not yet indicated for JAK2 inhibitor treatment between 2012 and 2016. The JAK2 V617F mutation was detected by pyrosequencing as a diagnostic work-up. The same samples were used for ddPCR to determine the correlation between assays and establish a detection sensitivity cut-off. Clinical and hematologic aspects were reviewed. RESULTS: Forty-two (75%) and 46 (82.1%) patients were positive for JAK2 V617F by pyrosequencing and ddPCR, respectively. The mean mutated allele frequency at diagnosis was 37.5±30.1% and was 40.7±31.2% with ddPCR, representing a strong correlation (r=0.9712, P<0.001). Follow-up samples were available for 12 patients, including eight that were JAK2 V617F-positive. Of these, mutational burden reduction after treatment was observed in six patients (75%), consistent with trends of hematologic improvement. CONCLUSIONS: Quantitative analysis of the JAK2 V617F mutation using ddPCR was highly correlated with pyrosequencing data and may reflect the clinical response to treatment.

A Novel 1.13 Mb Interstitial Duplication at 19q13.32 Causing Developmental Delay and Microcephaly in a Pediatric Patient: the First Asian Case Reports.

Only 6 patients with partial trisomy of the long arm of chromosome 19 (19q), caused by direct interstitial duplications, have been reported until today. Herein, we report a pediatric patient with a novel 1.13 Mb direct interstitial duplication within 19q13.32, which is the smallest fragment affected so far. A five-year old Korean boy of healthy parents presented with microcephaly, growth retardation, developmental delay, and craniofacial dysmorphism. Even though G-banded chromosome analysis at resolution of 550-band revealed normal karyotype, duplication of 1.13 Mb fragment within 19q13.32 was detected by array comparative genomic hybridization. Comparing with previously reported patients with pure duplication involving 19q as a sole chromosomal abnormality, our case showed the smallest duplication segment with relatively mild degree of clinical features. Our present case might serve as the landmark case among patients with 19q duplication for genotype-phenotype correlation study and further identification of critical region for 19q duplication abnormalities.