Clinical feature, GALC variant spectrum, and genotype-phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years.

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype-phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months-34 years) and the most common phenotype was adult-onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30-kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later-onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult-onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

What We Should Consider in Point of Care Blood Glucose Test; Current Quality Management Status of a Single Institution.

Background and Objectives: Point of care test (POCT) is generally performed by non-laboratory staff who often lack an understanding on the quality control and quality assurance programs. The purpose of this study was to understand the current status of quality management of point of care (POC) blood glucose testing in a single institution where non-laboratory staff perform the tests. Materials and Methods: From July to August 2020, management status of glucometer, test strips, quality control (QC) materials, quality assurance program, and operators' response to processing of displayed results was monitored in all Soonchunhyang University Bucheon hospital departments that performed POC blood glucose test. Results of the POC blood glucose test conducted from January 2019 to May 2020 were analyzed retrospectively. Results: A total 124 glucometers were monitored in 47 departments. Insufficient management of approximately 50% of blood sugar, test strips, and QC materials was observed. Although daily QC was conducted by 95.7% of the departments, the QC records were inaccurate. The method of recording test results varied with departments and operators. Various judgments and troubleshooting were performed on the unexpected or out of measurable range results, including some inappropriate processes. In POC blood glucose test results review, 4568 atypical results were identified from a total of 572,207 results. Conclusions: Sufficient training of the non-laboratory staff and ongoing assessment of competency through recertification is needed to maintain acceptable levels of POCT quality. In this study, various problems were identified in glucometer and reagent management, QC and post-analytic phase. We believe that these results provide meaningful basal information for planning effective operators' training and competency evaluation, and the development of an efficient POCT quality management system.

Effect of the Standardization of Diagnostic Tests on the Prevalence of Diabetes Mellitus and Impaired Fasting Glucose.

BACKGROUND: Without standardization of medical laboratory's testing practices, there is an increase in false diagnoses when relying on test results. However, the effect of test standardization is difficult to assess numerically. This study's purpose is to quantify the effect of the standardization level of a laboratory on the prevalence of diabetes mellitus (DM) and impaired fasting glucose (IFG). METHODS: Laboratories were classified into three levels: 'highly-standardized laboratory,' 'basically-standardized laboratory,' and 'non-standardized laboratory.' Based on the results of Korean External Quality Assessment Scheme (KEQAS), the cutoff values for diagnosis of DM and IFG were recalculated, given false positive and false negative rates. RESULTS: The prevalence of DM and IFG in the population as a whole was estimated using the 2013 Korea National Health and Nutrition Examination Survey (KNHANES) database. When the prevalence of DM from KNHANES was 11.88% (95% confidence interval [CI], 10.59%-13.17%), the proportion with a systematic false error ranged from 10.91% (95% CI, 9.65%-12.17%) to 13.09% (95% CI, 11.74%-14.45%). The prevalence of IFG varied from 13.59% (95% CI, 12.25%-14.91%) to 40.49% (95% CI, 38.54%-42.43%), in contrast to 24.58% (95% CI, 22.85%-26.31%) of the reference value. The prevalence of DM and IFG tended to be over- and under-estimated more as the laboratory standardization level became lower, respectively. CONCLUSION: Our study proved that standardization of clinical laboratory tests is an important factor affecting the prevalence estimation of national disease statistics based on the simulation using KNHANES data.

Novel GALT variations and mutation spectrum in the Korean population with decreased galactose-1-phosphate uridyltransferase activity.

BACKGROUND: Classic galactosemia (OMIM #230400) is an autosomal recessive metabolic disorder caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT, EC2.7.7.12) protein due to mutations in the GALT gene. The aim of this study was to provide a comprehensive and updated mutation spectrum of GALT in a Korean population. METHODS: Thirteen unrelated patients screened positive for galactosemia in a newborn screening program were included in this study. They showed a reduced GALT enzyme activity in red blood cells. Direct sequencing of the GALT gene and in silico analyses were done to evaluate the impact of novel variations upon GALT enzyme activity. We also reviewed previous reports for GALT mutations in Koreans. RESULTS: We identified six novel likely pathogenic variations including three missense (p.Ala101Asp, p.Tyr165His, and p.Pro257Thr), one small deletion/insertion [c.826_827delinsAA (p.Ala276Asn)], one frameshift (p.Asn96Serfs*5), and one splicing (c.378-1G > C) likely pathogenic variations. The most frequent variation was the Duarte variant (c.940A > G, 35.3%), followed by c.507G > C (p.Gln169His, 9.6%), among 34 Korean patients. Other mutations were widely scattered. None of the eight common mutations used for targeted mutation analysis in Western countries including p.Gln188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, c.253-2A > G, and a 5 kb deletion, had been found in Koreans until this study. CONCLUSIONS: Considering the mutation spectrum in Koreans, direct sequence analysis of entire GALT exons is recommended for accurate diagnosis. The mutations responsible for GALT deficiency in the Korean population were clearly different from those of other populations.

Multicenter comparison of analytical interferences of 25-OH vitamin D immunoassay and mass spectrometry methods by endogenous interferents and cross-reactivity with 3-epi-25-OH-vitamin D3.

Background: Vitamin D (vit-D) deficiency is highly prevalent in the Korean population, highlighting the need for accurate measurements. In this study, the interferences by endogenous and cross-reactive substances were compared between routine vit-D immunoassays and mass spectrometry (MS) methods. Methods: Two MS methods and 4 immunoassays from different manufacturers (Abbott, Beckman Coulter, Roche, Siemens) were compared. Residual samples that were icteric, lipemic, hemolyzed, high in rheumatoid factor, from myeloma patients, or patients undergoing hemodialysis were collected. Also, 4 levels of National Institute of Standards and Technology (NIST) Standard Reference Material 972a, and 12 samples serially spiked with 3-epi-25-OH-D3 were prepared. Results: Significant interferences were observed in hemolytic (Roche), icteric (Beckman and Siemens) and lipemic samples (all 4 immunoassays). Level 4 NIST material and 3-epi-25-OH-D3-spiked samples induced significant cross-reactivity, yielding higher total vit-D measurements in non-epimer-separating MS methods, and both the Beckman and Roche immunoassays. Conclusion: Most observed interferences were consistent with manufacturers' claims, but overall improvement of immunoassay bias limits is required. Awareness of potential interference is important to increase the accuracy of vit-D measurements. Moreover, care is due when interpreting vit-D results of newborns, infants and less commonly, pregnant women, who are known to have physiologically high levels of the highly cross-reactive 3-epi-25-OH-D3.

Urinary cystatin C levels as a diagnostic and prognostic biomarker in patients with acute kidney injury.

AIM: Acute kidney injury (AKI) is a frequent complication in critically ill patients and is associated with a high mortality. Clinicians have limited tools to predict the course of AKI at the time of serum creatinine increase. We evaluated the diagnostic and prognostic utility of urinary cystatin C (uCysC) in patients with AKI. METHODS: In this study, serum and uCysC and urinary creatinine (uCr) were measured in patients presenting with acute kidney injury. The patients were divided into two groups: those with prerenal AKI and those with an intrinsic AKI. Prerenal AKI was defined as a new-onset increase in serum creatinine (sCr) that resolved within 72 h and returned to the baseline kidney function level. Patients with intrinsic AKI were defined and classified according to the Acute Kidney Injury Network (AKIN) criteria. RESULTS: Of the total number of patients (n = 213), 40.4% (n = 86) were judged to have prerenal AKI and 59.6% (n = 127) intrinsic AKI. uCysC values and the uCysC/uCr ratio were significantly higher in intrinsic AKI versus prerenal AKI. In intrinsic AKI, the uCysC concentration increased with AKI severity. The uCysC/uCr ratio was significantly higher in the RRT group versus the non-RRT group (0.15 vs. 0.08, respectively; P = 0.037). In a multivariate analysis, the uCysC/uCr ratio was associated with in-hospital mortality (P = 0.019). CONCLUSIONS: uCysC level and the uCysC/uCr ratio were useful biomarkers of intrinsic AKI, and the uCysC/uCr ratio was predictive of in-hospital death in AKI patients.

Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism.

OBJECTIVE: To investigate thyroid-stimulating hormone receptor (TSHR) and thyroid peroxidase (TPO) mutations in Korean patients with primary congenital hypothyroidism (CH). CONTEXT: Congenital hypothyroidism is a common genetic disorder in which the majority of mutations occur in the TSHR and TPO genes. DESIGN: We examined the frequencies of TSHR and TPO mutations among Korean patients with primary CH. Furthermore, we explored the relationships between imaging findings and mutation status. PATIENTS: A total of 193 paediatric patients with nonsyndromic CH were enrolled in the present study. MEASUREMENTS: Patients with decreased (99m) Tc uptake were screened for TSHR mutations using Sanger sequencing, and those with increased uptake were screened for TPO mutations. The relationships between scintigraphic and ultrasonographic findings and mutation status were analysed. RESULTS: Thirteen (16·5%) of 79 patients with decreased (99m) Tc uptake were found to harbour TSHR mutations including G132R, G245S, R450H, R519C and F525S. The R450H mutation was present in 13 (72·2%) of 18 disease alleles. Seven (10·3%) of 68 patients with increased (99m) Tc uptake harboured TPO mutations including R189Q, K439E, G493S, C808LfsX72, A863T, R875Hfs and P883S. The TSHR and TPO mutations were observed only in patients with normal to slightly enlarged thyroid glands. CONCLUSIONS: This study identified underlying TSHR and TPO mutations in Korean patients with CH and revealed a possible relationship between imaging findings and mutation status. In addition, the low rate of mutation positivity suggests significant genetic heterogeneity of CH in the Korean population.

Improving the blood collection process using the active-phlebotomist phlebotomy system.

BACKGROUND: Because the number of patients requiring phlebotomy varies significantly at different times throughout the day, it is difficult to control wait times during peak times. We tried to solve this problem by changing from the conventional fixed-phlebotomist phlebotomy system (CFPPS), in which the phlebotomist waits for patients at a fixed location to the active-phlebotomist phlebotomy system (APPS), in which a phlebotomist goes to patients actively. We compared the productivity of these two systems. METHODS: After changing the system at our hospital, we measured the waiting time before seeing phlebotomy staff and compared it to a comparable hospital that uses CFPPS. We reviewed the phlebotomy count recorded in the laboratory information system before and after the system change. RESULTS: After the system change, the average waiting time for phlebotomy was 2.34 min (median 1 min) and the waiting time was less than 5 min in all time slots, except 7:00 to 7:30 a.m. The new system significantly decreased the waiting time. In addition, the maximum number of patients seen by a phlebotomist during the peak time was higher in the APPS. CONCLUSION: The APPS enhanced the productivity of the phlebotomist and reduced waiting time with limited human resources in a Korean hospital.

Schemes and Performance Evaluation Criteria of Korean Association of External Quality Assessment (KEQAS) for Improving Laboratory Testing.

External quality assessment (EQA) is important for evaluating clinical laboratories and enhancing their testing quality. EQA schemes are variable; thus, it is crucial that the EQA organizers share their experiences to continuously improve the EQA scheme. The Korean Association of External Quality Assessment Service (KEQAS) has been the leading, authorized EQA institute for the standardization and quality management of laboratory testing in Korean medical institutions since 1976. The EQA scheme underwent a major change in 2016, and the number of EQA programs increased significantly since then. The key changes implemented in EQA scheme include a fully computerized assessment to accelerate feedback and unification of the testing and reporting methods. We provide an overview of the EQA schemes and performance evaluation criteria of the KEQAS and suggest directions for achieving the global harmonization of EQA.

Standardization Status of Total Cholesterol Concentration Measurement: Analysis of Korean External Quality Assessment Data.

BACKGROUND: Total cholesterol concentration measurement is important in the diagnosis of dyslipidemia and evaluation of cardiovascular disease risk factors. Measurement reliability for obtaining an accurate total cholesterol concentration requires procedure standardization. We evaluated the standardization status for total cholesterol concentration measurement through Korean external quality assessment (EQA) data analysis. METHODS: This study involved 1,670 laboratories that participated in the EQA of total cholesterol concentration measurements in 2019 for 32 products from different manufacturers. The target concentrations of three quality control (QC) materials (samples A, B, and C) were measured using the reference method and compared with EQA data. The performance criteria for total cholesterol concentration measurement were based on the National Cholesterol Education Program guidelines, with ±3% inaccuracy. RESULTS: The target values and inaccuracies of the QC material based on the reference method measurements were 254.65±7.64, 108.30±3.25, and 256.29±7.69 mg/dL (6.59±0.20, 2.80±0.08, and 6.63±0.20 mmol/L) for samples A, B, and C, respectively. The performance criteria were not met in 42.7% laboratories for sample A, 68.4% of laboratories for sample B, and 38.0% laboratories for sample C. CONCLUSIONS: Despite significant efforts to accurately measure total cholesterol concentrations, further actions are needed for measurement standardization. Manufacturers reporting values that differ from target values should check calibrator traceability; additional efforts to accurately measure total cholesterol concentrations are required for laboratories that use products from these manufacturers.

Evaluation of the quick-clotting serum separator tube, VQ-Tube™, for clinical chemistry and thyroid hormone assays.

BACKGROUND: The type of blood collection tube affects specimen quality and laboratory results. Because plasma specimens have a shorter processing time compared with serum specimens, emergency biochemistry tests use plasma. However, serum specimens remain stable after centrifugation and show more accurate results than plasma. Therefore, a quick-clotting serum separator tube is expected to be useful for shorter turnaround times and accurate results. We evaluated a new quick-clotting serum separator tube VQ-Tube™ (AB Medical, Korea) for clinical chemistry and thyroid hormone assays. METHODS: One hundred volunteers from four university hospitals were recruited, and peripheral blood samples were collected in quick-clotting serum separator tube VQ-Tubes™ and the commonly used serum separator tube V-Tubes™. The obtained specimens were used for 16 clinical chemistry assays and three thyroid hormone assays. RESULTS: The differences (%) in the test results obtained from the samples in each tube satisfied the allowable difference ranges (19 assays). The differences in the test results between the tubes satisfied the desired specifications for accuracy except for the glucose results (2.75%). The paired t-test revealed significant differences between the results of six assays, but each set of results showed a good correlation. Samples were visually inspected for serum clarity and gel barrier integrity, and incomplete clotting reactions and haemolysed serum were not observed. CONCLUSIONS: The new quick-clotting VQ-Tube™ demonstrated reliable test results compared with the commonly used serum separator tube V-Tube™. This quick-clotting tube will provide fast test results with adequately separated serum specimens, especially for patients who need fast tests.

Immunosuppressive Drug Measurement by Liquid Chromatography Coupled to Tandem Mass Spectrometry: Interlaboratory Comparison in the Korean Clinical Laboratories.

BACKGROUND: Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is increasingly used for immunosuppressive drug tests. However, most LC-MS/MS tests are laboratory-developed and their agreement is unknown in different Korean laboratories. This interlaboratory comparison study evaluated test reproducibility and identified potential error sources. METHODS: Test samples containing three concentrations of tacrolimus, sirolimus, everolimus, cyclosporine, and mycophenolic acid were prepared by pooling surplus samples from patients undergoing routine therapeutic drug monitoring and tested in duplicate in the participating 10 clinical laboratories. Reconstitution and storage experiments were conducted for the commonly used commercial calibrator set. The robust estimators of reproducibility parameters were calculated. Spearman's rank correlation coefficient (rho, ρ) was used to evaluate the correlation between drugs. Multiple linear regression was used to determine whether the experimental conditions alter the calibration curves. RESULTS: The reproducibility coefficient of variation exceeded 10% only for sirolimus concentrations 1 and 2 (10.8% and 12.5%, respectively) and everolimus concentrations 1 and 2 (12.3% and 11.4%, respectively). The percent difference values showed weak correlations between sirolimus and everolimus (ρ=0.334, P =0.175). The everolimus calibration curve slope was significantly altered after reconstitution following prolonged 5°C storage (P =0.015 for 14 days; P =0.025 for 28 days); the expected differences at 6 ng/mL were 0.598% for 14 days and 0.384% for 28 days. CONCLUSIONS: LC-MS/MS test reproducibility for immunosuppressive drugs seems to be good in the Korean clinical laboratories. Continuous efforts are required to achieve test standardization and harmonization, especially for sirolimus and everolimus.

Clinical, biochemical, and genetic analysis of a Korean neonate with hereditary tyrosinemia type 1.

BACKGROUND: Hereditary tyrosinemia type 1 (HT1; MIM 276700) is caused by mutations in the fumarylaceto-acetate hydrolase (FAH) gene, and is the most severe disorder associated with the tyrosine catabolic pathway. HT1 is a very rare disorder and no genetically confirmed case of HT1 in Korea has yet been reported. In this study, we present a Korean neonate with clinical and biochemical features of HT1. METHODS: A female neonate was admitted to our hospital for further work-up of an abnormal newborn screening test. We analyzed amino acids and organic acids in the patient's blood and urine. To confirm the presence of the genetic abnormality, all the coding exons of the FAH gene and the flanking introns were amplified by polymerase chain reaction (PCR). RESULTS: The patient's newborn screening test revealed increased concentrations of methionine and tyrosine. Subsequent urine organic acid analysis showed increased urinary excretion of 4-hydroxyphenyllactate, 4-hydroxyphenylpyruvate, succinate, and succinylacetone. Gap-PCR and sequence analysis of the FAH gene revealed a homozygous large deletion mutation encompassing exons 12-14. The patient's parents were not consanguineous but were heterozygous carriers of the same mutation. CONCLUSIONS: The patient had a novel, large deletion mutation of FAH and is the first report of genetically confirmed HT1 in Korea.

Association between vitamin D level at birth and respiratory morbidities in very-low-birth-weight infants.

PURPOSE: This study aimed to evaluate vitamin D status at birth in very-low-birth-weight infants (VLBWIs: <1,500 g) and to determine the association between vitamin D level and respiratory morbidity. METHODS: A retrospective study was conducted at Soonchunhyang University Bucheon Hospital between November 2013 and November 2017. We collected blood samples and data on respiratory morbidity from 230 VLBWIs on the first day of life. Patients who were transferred to other hospitals (n=19), died before 36 weeks of gestational age (n=18), or whose blood samples were not collected immediately after birth (n=5) were excluded. Finally, 188 patients were enrolled. VLBWIs with different vitamin D levels were compared with respect to demographic features, maternal diseases, respiratory morbidities, and other neonatal diseases. RESULTS: The mean serum vitamin D level, as measured by 25-hydroxyvitamin D (25(OH)D), was 13.4± 9.3 ng/mL. The incidence of vitamin D deficiency (<20 ng/mL) was 79.8%, and 44.1% of preterm infants had severe vitamin D deficiency (<10 ng/mL). Logistic analysis shows that a low serum 25(OH)D level (<20 ng/mL) was a risk factor for respiratory distress syndrome (odds ratio [OR], 4.32; P=0.010) and bronchopulmonary dysplasia (OR, 4.11; P=0.035). CONCLUSION: The results showed that 79.8% of preterm infants in this study had vitamin D deficiency at birth. Low vitamin D status was associated with respiratory morbidity, but the exact mechanism was unknown. Additional studies on the association between vitamin D level and neonatal morbidity are required.

Use of Liquid Chromatography-Tandem Mass Spectrometry for Clinical Testing in Korean Laboratories: a Questionnaire Survey.

BACKGROUND: The use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has substantially increased in clinical laboratories worldwide. To assess the status of clinical LC-MS/MS testing in Korean laboratories, a questionnaire survey was performed by the Clinical Mass Spectrometry Research Committee of the Korean Society of Clinical Chemistry. METHODS: The questionnaire was distributed to 19 clinical laboratories performing clinical LC-MS/MS from April to May 2018. It asked about general characteristics of the laboratory and commonly utilized clinical LC-MS/MS tests: newborn screening, tacrolimus test, vitamin D test, and plasma metanephrine test. Frequency analysis and other statistical analyses were performed. RESULTS: A total of 17 laboratories responded. The median number of LC-MS/MS instruments, laboratory medicine physicians, and technicians in each laboratory was three, one, and two, respectively. Nine laboratory directors had >10 years of experience with clinical LC-MS/MS. For each LC-MS/MS test, at least two concentrations of QC materials were measured every 24 hours during clinical testing, and all laboratories used QC acceptability criteria based on their established QC means and SDs. All laboratories participated in an external quality assessment program. However, there was inter-laboratory variability in sample preparation methods, instruments, reagents, internal standards, and calibrators. CONCLUSIONS: LC-MS/MS has been successfully introduced in Korean clinical laboratories and is used within a quality framework. Further efforts for harmonization on a nationwide basis could facilitate the widespread use of LC-MS/MS.

Development of Statistical Software for the Korean Laboratory Accreditation Program Using R Language: LaboStats.

BACKGROUND: In Korea, the Korean Laboratory Accreditation Program (KLAP) has set minimum standards for verification of clinical test performance. This verification process is time-consuming and labor-intensive when performed manually. We developed a free, statistical software program for KLAP, using the R language (R Foundation for Statistical Computing, Vienna, Austria). METHODS: We used CLSI guidelines for the algorithm. We built graphic user interfaces, including data input, with Embarcadero Delphi EX4 (Embarcadero Technologies, Inc., Texas, USA). The R Base Package and MCR Package for Method Comparison Regression were used to implement statistical and graphical procedures. RESULTS: Our program LaboStats has six modules: parallel test, linearity, method comparison, precision, reference interval, and cutoff. Data can be entered into the field either manually or by copying and pasting from an MS Excel worksheet. Users can print out precise reports. CONCLUSIONS: LaboStats can be useful for evaluating clinical test performance characteristics and preparing documents requested by KLAP.

Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria.

Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify approximately 14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects.

Mutation of Glu78 of the AVP-NPII gene impairs neurophysin as a carrier protein for arginine vasopressin in a family with neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI; OMIM 192340) is a rare inherited disorder with an autosomal dominant inheritance pattern. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). We report a Korean kindred in whom FNDI is associated with a novel deletion mutation in exon 2 of the AVP-NPII gene encoding the neurophysin II moiety. An 18-yr-old man with polyuria and polydipsia was shown to have central diabetes insipidus by using the water deprivation test. Four family members were suspected to have symptomatic vasopressin-deficient diabetes insipidus. Direct sequencing of the AVP-NPII gene showed a heterozygous GAG deletion mutation in exon 2, which results in in-frame deletion of glutamic acid (c.232_234delGAG; p.Glu78del). The mutation was predicted to yield an abnormal AVP precursor lacking Glu78 (E78) in its neurophysin II moiety. Because Glu78 is essential for neurophysin II molecules to form a salt bridge with AVP, the function of neurophysin as a carrier protein for AVP would be impaired. The proband's mother and sister have the same mutation. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the appropriate expression of vasopressin.