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  • Original Article2021-07-01 Diagnostic Genetics

    Accuracy and Performance Evaluation of Triplet Repeat Primed PCR as an Alternative to Conventional Diagnostic Methods for Fragile X Syndrome

    Hyunjung Gu , M.D., Man Jin Kim , M.D., Dahae Yang , M.D., Ji Yun Song, M.T., Sung Im Cho , M.T., Sung Sup Park , M.D., Ph.D., and Moon-Woo Seong , M.D., Ph.D.

    Ann Lab Med 2021; 41(4): 394-400

    Abstract : Background: Conventional diagnosis of fragile X syndrome (FXS) is based on a combination of fragment analysis (FA) and Southern blotting (SB); however, this diagnostic approach is time- and labor-intensive and has pitfalls such as the possibility of missing large number alleles. Triplet repeat primed PCR (TP-PCR) is a current alternative used to overcome these limitations. We evaluated the diagnostic usefulness of TP-PCR compared with the conventional diagnostic protocol consisting of FA and/or SB in terms of allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers. Methods: From November 2013 to March 2018, 458 patients (326 males, 132 females) were simultaneously examined using FA and/or SB and TP-PCR by detecting CGG repeat numbers in FMR1 gene and diagnosed as per American College of Medical Genetics guidelines. Results: The TP-PCR results showed high concordance with the FA and/or SB results for all three aspects (allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers). TP-PCR detected CGG expansions ≥200 in all full mutation (FM) allele cases in male patients, as well as both the normal allele (NL) and FM allele in female carriers. In premutation (PM) allele carriers, the TP-PCR results were consistent with the FA and/or SB results. In terms of zygosity concordance in female genetic carriers, 12 NL cases detected by TP-PCR showed a merged peak consisting of two close heterozygous peaks; however, this issue was resolved using a 10-fold dilution. Conclusions: TP-PCR may serve as a reliable alternative method for FXS diagnosis.

  • Review Article2022-03-01 Diagnostic Genetics

    Clinical Practice Guidelines for Pre-Analytical Procedures of Plasma Epidermal Growth Factor Receptor Variant Testing

    Saeam Shin , M.D., Ph.D., Hye In Woo , M.D., Ph.D., Jong-Won Kim , M.D., Ph.D., Yoonjung Kim M.D. , Ph.D., Kyung-A Lee , M.D., Ph.D.

    Ann Lab Med 2022; 42(2): 141-149

    Abstract : Standardization of cell-free DNA (cfDNA) testing processes is necessary to obtain clinically reliable results. The pre-analytical phase of cfDNA testing greatly influences the results because of the low proportion and stability of circulating tumor DNA (ctDNA). In this review, we provide evidence-based clinical practice guidelines for pre-analytical phase procedures of plasma epidermal growth factor receptor gene (EGFR) variant testing. Specific recommendations for pre-analytical procedures were proposed based on evidence from the literature and our experimental data. Standardization of pre-analytical procedures can improve the analytical performance of cfDNA testing.

  • Review Article2022-05-01 Diagnostic Genetics

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

    Namhee Kim , M.D., Sun-Young Kong , M.D., Ph.D., Jongha Yoo , M.D., Ph.D., Do-Hoon Kim , M.D., Ph.D., Soo Hyun Seo , M.D., and Jieun Kim , M.D., Ph.D.

    Ann Lab Med 2022; 42(3): 314-320

    Abstract : 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.

  • Original Article2021-07-01 Diagnostic Genetics

    Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver–Russell Syndrome

    Soo Yeon Kim , M.D., Chang Ho Shin , M.D., Young Ah Lee , M.D., Ph.D., Choong Ho Shin , M.D., Ph.D., Sei Won Yang , M.D., Ph.D., Tae-Joon Cho , M.D., Ph.D., and Jung Min Ko , M.D., Ph.D.

    Ann Lab Med 2021; 41(4): 401-408

    Abstract : Background: Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS. Methods: Twenty-eight patients who met≥3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, MEST on chromosome 7q32.2, and MEG3 on chromosome 14q32.2 was performed. Results:. Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N=14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N=3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment. Conclusions: NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.

  • Original Article2021-09-01 Diagnostic Genetics

    Expanding the Non-Invasive Diagnosis of Acute Rejection in Kidney Transplants Through Detection of Donor-Derived DNA in Urine: Proof-of-Concept Study

    Jieun Kim , M.D., Ph,D., Dong-Moung Kim , B.A., Yu Jin Park , M.D., Ph.D., Seung-Tae Lee , M.D., Ph,D., Hyon-Suk Kim , M.D., Ph,D., Myoung Soo Kim , M.D., Ph.D., Beom Seok Kim , M.D., Ph.D., and Jong Rak Choi , M.D., Ph.D.

    Ann Lab Med 2021; 41(5): 469-478

    Abstract : Background: Approximately 10%-20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR. Methods: Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis. Results: There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81-1.00) and a high negative predictive value of 100.0%. Conclusions: Although the dd-DNA-based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.

  • Original Article2022-01-01 Diagnostic Genetics

    Clinical Utility of Methylation-Specific Multiplex Ligation-Dependent Probe Amplification for the Diagnosis of Prader–Willi Syndrome and Angelman Syndrome

    Boram Kim , M.D., Yongsook Park , M.T., Sung Im Cho , M.T., Man Jin Kim , M.D., Jong-Hee Chae , M.D., Ph.D., Ji Yeon Kim , M.D., Ph.D., Moon-Woo Seong , M.D., Ph.D., and Sung Sup Park , M.D., Ph.D.

    Ann Lab Med 2022; 42(1): 79-88

    Abstract : Background: Prader–Willi syndrome (PWS) and Angelman syndrome (AS) are genomic imprinting disorders that are mainly caused by a deletion on 15q11-q13, the uniparental disomy of chromosome 15, or an imprinting defect. We evaluated the utility of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a diagnostic tool and for demonstrating the relationship between molecular mechanisms and clinical presentation. Methods: We performed MS-MLPA using DNA samples from 93 subjects (45 PWS, 24 AS, and 24 non-PWS/AS controls) who had previously undergone MS-PCR for the diagnosis of PWS/AS. We compared the results of both assays, and patients’ clinical phenotypes were reviewed retrospectively. Results: MS-MLPA showed a 100% concordance rate with MS-PCR. Among the 45 PWS patients, 26 (57.8%) had a deletion of 15q11-q13, and the others (42.2%) had uniparental disomy 15 or an imprinting defect. Among the 24 AS patients, 16 (66.7%) had a deletion of 15q11-q13, 7 AS patients (29.2%) had uniparental disomy 15 or an imprinting defect, and one AS patient (4.2%) showed an imprinting center deletion. Conclusions: MS-MLPA has clinical utility for the diagnosis of PWS/AS, and it is superior to MS-PCR in that it can identify the molecular mechanism underlying the disease.

  • Letter to the Editor2021-07-01 Diagnostic Genetics

    The First Korean Case of NUP98-NSD1 and a Novel SNRK-ETV6 Fusion in a Pediatric Therapy-related Acute Myeloid Leukemia Patient Detected by Targeted RNA Sequencing

    Ha Jin Lim , M.D., Jun Hyung Lee , M.D., Young Eun Lee , M.S., Hee-Jo Baek , M.D., Hoon Kook , M.D., Ju Heon Park , M.D., Seung Yeob Lee , M.D., Hyun-Woo Choi , M.D., Hyun-Jung Choi , M.D., Seung-Jung Kee , M.D., Jong Hee Shin , M.D., and Myung Geun Shin , M.D.

    Ann Lab Med 2021; 41(4): 443-446
  • Letter to the Editor2021-05-01 Diagnostic Genetics

    A Novel De Novo Heterozygous ARID1A Missense Variant Cluster in cis c.[5954C>G;6314C>T;6334C>T;6843G>C] causes a Coffin–Siris Syndrome

    Cha Gon Lee , M.D., Ph.D. and Chang-Seok Ki , M.D., Ph.D.

    Ann Lab Med 2021; 41(3): 350-353
  • Letter to the Editor2021-09-01 Diagnostic Genetics

    Hb Murcia (β118(G19)His>Gln): A New Hemoglobin Variant Found in a Spanish Woman

    Beatriz González Fernández , M.S., José Bartolomé Nieto Campuzano , M.D., Dolores García Rocamora , M.D., Jorge M Nieto , M.S., Fernando Ataúlfo González Fernández , M.D., Ana Villegas , M.D., Ph.D., Celina Benavente Cuesta , M.D., and Paloma Ropero , Ph.D.

    Ann Lab Med 2021; 41(5): 514-517
  • Original Article2022-05-01 Diagnostic Genetics

    Genetic Counseling and Long-Term Surveillance Using a Multidisciplinary Approach in von Hippel–Lindau Disease

    Sun Joo Yoon , M.D. , Won Kyung Kwon , M.D., Ph.D., Geehay Hong , M.D., Ja-Hyun Jang , M.D., Ph.D., Byong Chang Jeong , M.D., Ph.D., Jae Hyeon Kim , M.D., Ph.D., and Jong-Won Kim , M.D., Ph.D.

    Ann Lab Med 2022; 42(3): 352-357

    Abstract : Background: von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by variants of the VHL tumor suppressor gene (VHL). Early detection and treatment are essential to prevent morbidity and mortality. We evaluated the effectiveness of surveillance strategies and the utility of a VHL clinic with a multidisciplinary team for the first time in Korea. Methods: The VHL clinic was organized at the Samsung Medical Center in 2011 and consisted of a multidisciplinary team, including an endocrinologist, urologist, general surgeon, neurosurgeon, ophthalmologist, otolaryngologist, and radiologist. Biochemical and imaging surveillance and personalized genetic counseling were conducted at the VHL clinic and patients were referred to the necessary departments upon detection of disease manifestation. We divided the patients in three groups (I–III) based on their compliance to VHL clinic attendance. Results: Between 2011 and 2018, 50 VHL patients were identified by VHL molecular analysis and referred to the VHL clinic. Most patients regularly participated in imaging of the central nervous system (43/50, 86.0%) and of the abdomen (46/50, 92.0%). However, there were differences in compliance to determination of the catecholamine level, audiometry, and ophthalmic examination among the three groups. Conclusions: We present the results of using a multidisciplinary team approach and showed that the VHL clinic strategy is useful for the comprehensive surveillance and management of VHL disease. We hope that VHL clinics will be widely set up in hospitals to improve prognosis in patients with VHL.

Annals of Laboratory Medicine
Journal Information July, 2023
Vol.43 No.4
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