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 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 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.
Original Article2023-01-01 Diagnostic Genetics
Jaehyeok Jang , M.D., Yoonjung Kim , M.D., Ph.D., Jae-Hoon Kim , M.D., Ph.D., Sun-Mi Cho , M.D., and Kyung-A Lee , M.D., Ph.D.
Abstract : Background: BRCA testing is necessary for establishing a management strategy for ovarian cancer. Several BRCA testing strategies, including germline and somatic testing, are implemented in clinical practice in Korea. We aimed to comparatively evaluate their cost-effectiveness from patients’ perspective. Methods: We developed a decision model comprising five BRCA testing strategies implemented in Korea: (1) germline testing first, followed by somatic tumor testing for patients without a germline variant; (2) somatic testing first, followed by germline testing for patients with a variant detected by somatic testing; (3) both germline and somatic testing; (4) germline testing alone; and (5) somatic testing alone, with no testing as the comparator. One-way sensitivity analysis was conducted to test the uncertainty of key parameters. Results: Assuming a willingness-to-pay of $20,000 per progression-free life-year gain (PF-LYG), all five strategies were considered cost-effective. Strategy 4 was the most cost-effective option, with an incremental cost-effectiveness ratio (ICER) of $2,547.7 per PF-LYG, followed by strategy 1, with an ICER of $3,978.4 per PF-LYG. Even when the parameter values were varied within the possible range, the ICERs of all strategies did not exceed the willingness-to-pay threshold. Conclusions: Considering the importance of knowing a patient’s BRCA gene status, germline testing first, followed by somatic testing, may be a reasonable option.
Original Article2023-01-01 Diagnostic Genetics
Yoonjung Kim , M.D., Ph.D., Inho Park , Ph.D., Boyeon Kim , M.D., Ph.D., Yu Jeong Choi , M.D., Seoung Chul Oh , M.T., M.S., and Kyung-A Lee , M.D., Ph.D.
Abstract : Background: Following success of the phase III PROfound trial, the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib was approved by the US Food and Drug Administration in May 2020 for adult patients with deleterious homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). As locally adopted multigene panel next-generation sequencing (NGS) assays for selecting PARP inhibitor candidates have not been thoroughly evaluated, we compared the analytical performance of the FoundationOne CDx (Foundation Medicine, Inc., Cambridge, MA, USA) (central laboratory) and other NGS assays (local laboratory) with samples from the PROfound trial in Korea. Methods: One hundred PROfound samples (60 HRR mutation [HRRm] cases and 40 non-HRRm cases) were analyzed. The results of HRR gene mutation analysis were compared between the FoundationOne CDx and two other NGS assays [SureSelect Custom Design assay (Agilent Technologies, Inc., Santa Clara, CA, USA) and Oncomine Comprehensive assay (Thermo Fisher Scientific, Inc., Waltham, MA, USA)]. Results: The positive percent agreement for single nucleotide variants (SNVs) and insertion/deletions (indels) between the central laboratory and local laboratory was 98.7%–100.0%. The negative percent agreement and overall percent agreement (OPA) for SNVs and indels between central and local laboratories were both 100%. Compared with that of the FoundationOne CDx assay, the OPA for copy number variations of the Oncomine Comprehensive and SureSelect Custom assays reached 99.8%–100%. Most mCRPC patients harboring a deleterious genetic variant were successfully identified with both local laboratory assays. Conclusions: The NGS approach at a local laboratory showed comparable analytical performance for identifying HRRm status to the FoundationOne CDx assay used at the central laboratory.
Letter to the Editor2021-11-01 Diagnostic Genetics
Yoomi Yeo , M.D., Jong Eun Park , M.D., Ph.D., and Hyuk Sung Kwon , M.D., Ph.D.
Letter to the Editor2023-03-01 Diagnostic Genetics
Jihoon G. Yoon , M.D., Ph.D., Seungbok Lee , M.D., Ph.D., Sheehyun Kim , M.D., Man Jin Kim , M.D., Ph.D., Yoon Hwan Chang , M.D., Ph.D., Jin Kyun Park , M.D., Ph.D., Dong-Yeop Shin , M.D., Ph.D., and Jangsup Moon , M.D., Ph.D.
Brief Communication2022-03-01 Diagnostic Genetics
Ja-Hyun Jang , M.D. Ph.D., Sun Joo Yoon , M.D., Sun-Kyung Kim , M.T., Jin Whan Cho , M.D., and Jong-Won Kim , M.D.
Abstract : Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disease caused by abnormal CAG repeat expansion in the ataxin 1 gene (ATXN1). The presence of CAT interruption(s) is important for diagnosing SCA1 in patients with 39–44 repeat alleles, as only uninterrupted alleles are considered abnormal. Determining the CAT interruption status might also be important for patients with >44 repeats, as the length of the longest uninterrupted CAG repeat stretch has been correlated with age at SCA1 onset. We detected CAT interruption(s) in the archived samples of Korean SCA1 patients using a traditional restriction enzyme method and validated the usefulness of a fluorescence-based tethering PCR procedure. Among the 2,312 alleles analyzed from 1,156 patients, we found 17 expanded alleles with ≥39 repeats, 71% of which harbored 39–44 repeats. Restriction enzyme method of six samples (four with 39–44 repeats and two with >44 repeats) revealed that none of the expanded alleles had CAT interruption(s). Tethering PCR showed the characteristic electropherogram pattern expected without CAT interruption(s). Along with the enzyme restriction method, tethering PCR can be applied to determine the number of allele repeats and provide information on CAT interruption(s) in clinical laboratories.
Original Article2022-11-01 Diagnostic Genetics
Hwa Young Kim , M.D., Ph.D., Choong Ho Shin , M.D., Ph.D., Young Ah Lee , M.D., Ph.D., Chang Ho Shin , M.D., Gu-Hwan Kim , Ph.D., and Jung Min Ko , M.D., Ph.D.
Abstract : Background: Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype–phenotype correlations in Korean children with BWS. Methods: Forty children with BWS with proven genetic or epigenetic defects in the 11p15.5 region were included. The phenotype was scored using the BWS consensus scoring system. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), bisulfite pyrosequencing, a single-nucleotide polymorphism microarray, and CDKN1C sequencing were used for confirmative diagnosis. Results: Patients met the criteria for genetic testing, with a mean clinical score of 5.4±2.0. Methylation alterations were consistent between MS-MLPA and bisulfite pyrosequencing in all patients. Twenty-six patients (65.0%) had IC2 loss of methylation (IC2-LoM), 11 (27.5%) had paternal uniparental disomy (patUPD), and one (2.5%) had IC1 gain of methylation. Macroglossia and external ear anomalies were more common in IC2-LoM than in patUPD, and lateralized overgrowth was more common in patUPD than in IC2-LoM (all P
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