Review Article2022-03-01
Diagnostic Genetics
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.
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
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.
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
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.
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
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.
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
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.
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.
Original Article2021-01-01
Diagnostic Genetics
Jianyan Pan , Ph.D., Chunhua Zhang , Ph.D., Yanling Teng , M.S., Sijing Zeng , M.S., Siyi Chen , Ph.D., Desheng Liang , M.D., Ph.D., Zhuo Li , Ph.D., and Lingqian Wu , M.D., Ph.D.
Abstract : Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder mainly caused by homozygous deletions that include exon 7 of the survival motor neuron 1 (SMN1) gene. A nearby paralog gene, SMN2, obstructs the specific detection of SMN1. We optimized a duplexed real-time PCR approach using locked nucleic acid (LNA)-modified primers to specifically detect SMN1. Methods: An LNA-modified primer pair with 3´ ends targeting SMN1 specific sites c.835-44g and c.840C was designed, and its specificity was examined by real-time PCR and Sanger Sequencing. A duplexed real-time PCR approach for amplifying SMN1 and control gene albumin (ALB) was developed. A randomized double-blind trial with 97 fresh peripheral blood samples and 25 dried blood spots (DBS) was conducted to evaluate the clinical efficacy of the duplexed approach. This new approach was then used to screen 753 newborn DBS. Results: The LNA-modified primers exhibited enhanced specificity and 6.8% increased efficiency for SMN1 amplification, compared with conventional primers. After stabilizing the SMN1 test by optimizing the duplexed real-time PCR approach, a clinical trial validated that the sensitivity and specificity of our new approach for detecting SMA patients and carriers was 100%. Using this new approach, 15 of the screened 753 newborns were identified as carriers via DBS, while the rest were identified as normal individuals. These data reveal a carrier rate of 1.99% in Hunan province, South Central China. Conclusions: We have developed a novel, specific SMN1 detection approach utilizing real-time PCR with LNA-modified primers, which could be applied to both prenatal carrier and newborn screening.
Letter to the Editor2021-07-01
Diagnostic Genetics
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.
Letter to the Editor2021-09-01
Diagnostic Genetics
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.
Original Article2022-05-01
Diagnostic Genetics
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.
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.
Letter to the Editor2021-03-01
Diagnostic Genetics
Eun Sil Kim , M.D., Ju Sun Song , M.D., Chang-Seok Ki , M.D., Ph.D., Yon Ho Choe , M.D., Ph.D., and Ben Kang , M.D.
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