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Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: A prenatal diagnosis report.

In Ae CHO ; Ji Kwon PARK ; Jong Chul BAEK ; A Na HA ; Min Young KANG ; Jae Ik LEE ; Ji Eun PARK ; Jeong Kyu SHIN ; Won Jun CHOI ; Soon Ae LEE ; Jong Hak LEE ; Won Young PAIK

Journal of Genetic Medicine.2015;12(2):123-127. doi:10.5734/JGM.2015.12.2.123

Distal limb deformities are congenital malformations with phenotypic variability and high genetic heterogeneity. Split hand/foot malformation, also known as ectrodactyly, is a congenital limb malformation characterized by a defect of the central rays of the hands and/or feet. Split hand/foot malformation with long-bone deficiency (SHFLD) is a rare condition related to a 17p13.3 duplication. Recently, genomic duplications encompassing BHLHA9 have been associated with SHFLD. We report a case of SHFLD presenting with campomelia of the right femur, bilateral agenesis of fibulae, bilateral club feet, and oligosyndactyly of the hands and feet, that was associated with a 17p13.3 duplication, as determined prenatally using array comparative genomic hybridization.
Comparative Genomic Hybridization ; Congenital Abnormalities ; Extremities ; Femur ; Fibula ; Foot ; Genetic Heterogeneity ; Hand ; Prenatal Diagnosis*

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Noninvasive prenatal test for the pregnancy with Turner syndrome mosaicism 45, X/47, XXX: A case report.

Ji Hye KIM ; Gun Ho LEE ; Dong Hyun CHA ; Eun Hae CHO ; Yong Wook JUNG

Journal of Genetic Medicine.2015;12(2):118-122. doi:10.5734/JGM.2015.12.2.118

Noninvasive prenatal test (NIPT) is a novel screening method for the diagnosis of fetal chromosomal aneuploidies. NIPT is based on technology that detects cell-free fetal DNA in maternal plasma and analyzes it with massively parallel sequencing technology to determine whether the fetus is at risk of trisomy 21, trisomy 18, trisomy 13 or sex chromosome abnormalities (SCAs). NIPT has been reported to have sensitivity of 99% and a false positive rate of less than 1% for detecting trisomy 21 and trisomy 18. Although extension of the application of NIPT to other SCAs has been attempted, there are concerns in extending NIPT to SCAs because of maternal or fetal mosaicism, undetected maternal SCAs, and multiple pregnancies. Recently, we assessed a pregnancy with the rare Turner syndrome mosaicism 45, X/47, XXX, which was reported as 45, X with NIPT. We present the case here and briefly review the current literatures on NIPT in testing for fetal monosomy X. To the best of our knowledge, this is the first report of the 45, X/47, XXX mosaicism in Korea to be reported as 45, X by NIPT with whole genome sequencing. This case report will provide valuable information for counseling women who want to undergo NIPT.
Aneuploidy ; Counseling ; Diagnosis ; DNA ; Down Syndrome ; Female ; Fetus ; Genome ; High-Throughput Nucleotide Sequencing ; Humans ; Korea ; Mass Screening ; Mosaicism* ; Plasma ; Pregnancy* ; Pregnancy, Multiple ; Prenatal Diagnosis ; Sex Chromosome Aberrations ; Trisomy ; Turner Syndrome*

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Identification of causative mutations in patients with Leigh syndrome and MERRF by mitochondrial DNA-targeted next-generation sequencing.

Hyun Dae HONG ; Eunja KIM ; Soo Hyun NAM ; Da Hye YOO ; Bum Chun SUH ; Byung Ok CHOI ; Ki Wha CHUNG

Journal of Genetic Medicine.2015;12(2):109-117. doi:10.5734/JGM.2015.12.2.109

PURPOSE: Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make their exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mitochondrial DNA (mtDNA) mutations in 2 Korean families with myoclonic epilepsy with ragged-red fibers (MERRF) and Leigh syndrome, respectively. MATERIALS AND METHODS: Whole mtDNAs were sequenced by the method of mtDNA-targeted next-generation sequencing (NGS). RESULTS: Two causative mtDNA mutations were identified from the NGS data. An m.8344A>G mutation in the tRNA-Lys gene (MT-TK ) was detected in a MERRF patient (family ID: MT132), and an m.9176T>C (p.Leu217Pro) mutation in the mitochondrial ATP6 gene (MT-ATP6) was detected in a Leigh syndrome patient (family ID: MT130). Both mutations, which have been reported several times before in affected individuals, were not found in the control samples. CONCLUSION: This study suggests that mtDNA-targeted NGS will be helpful for the molecular diagnosis of genetically heterogeneous mitochondrial diseases with complex phenotypes.
Classification ; Diagnosis ; DNA, Mitochondrial ; Humans ; Leigh Disease* ; MERRF Syndrome* ; Mitochondrial Diseases ; Phenotype

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Noninvasive fetal RHD genotyping using cell-free fetal DNA incorporating fetal RASSF1A marker in RhD-negative pregnant women in Korea.

Sung Hee HAN ; Young Ho YANG ; Jae Song RYU ; Young Jin KIM ; Kyoung Ryul LEE

Journal of Genetic Medicine.2015;12(2):100-108. doi:10.5734/JGM.2015.12.2.100

PURPOSE: Conventional methods for the prenatal detection of fetal RhD status involve invasive procedures such as fetal blood sampling and amniocentesis. The identification of cell-free fetal DNA (cffDNA) in maternal plasma creates the possibility of determining fetal RhD status by analyzing maternal plasma DNA. However, some technical problems still exist, especially the lack of a positive control marker for the presence of fetal DNA. Therefore, we assessed the feasibility and accuracy of fetal RHD genotyping incorporating the RASSF1A epigenetic fetal DNA marker from cffDNA in the maternal plasma of RhD-negative pregnant women in Korea. MATERIALS AND METHODS: We analyzed maternal plasma from 41 pregnant women identified as RhD-negative by serological testing. Multiplex real-time PCR was performed by amplifying RHD exons 5 and 7 and the SRY gene, with RASSF1A being used as a gender-independent fetal epigenetic marker. The results were compared with those obtained by postnatal serological analysis of cord blood and gender identification. RESULTS: Among the 41 fetuses, 37 were RhD-positive and 4 were RhD-negative according to the serological analysis of cord blood. There was 100% concordance between fetal RHD genotyping and serological cord blood results. Detection of the RASSF1A gene verified the presence of cffDNA, and the fetal SRY status was correctly detected in all 41 cases. CONCLUSION: Noninvasive fetal RHD genotyping with cffDNA incorporating RASSF1A is a feasible, reliable, and accurate method of determining fetal RhD status. It is an alternative to amniocentesis for the management of RhD-negative women and reduces the need for unnecessary RhIG prophylaxis.
Amniocentesis ; DNA* ; Epigenomics ; Exons ; Female ; Fetal Blood ; Fetus ; Genes, sry ; Genetic Markers ; Humans ; Korea* ; Plasma ; Pregnant Women* ; Prenatal Diagnosis ; Real-Time Polymerase Chain Reaction ; Serologic Tests

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Evaluating the results of the Momguard noninvasive prenatal test.

Hae Jin HU ; Young Jun KWON ; Mijin OH ; Jihun KIM ; Dae Yeon CHO ; Dong Hee SEO

Journal of Genetic Medicine.2015;12(2):96-99. doi:10.5734/JGM.2015.12.2.96

PURPOSE: To evaluate the performance of the Momguard noninvasive prenatal test by tracing the 'screen positive' results based on preliminary samples from Korean cohorts. MATERIALS AND METHODS: This preliminary study is based on data collected by the LabGenomics Clinical Laboratory (Seongnam, Korea) with informed consent. Only pregnant women who underwent both the Momguard test and karyotyping were included in this study. Momguard test results were compared with those of the karyotyping analysis. RESULTS: Among the 38 cases with 'screen positive' results by Momguard, 30 cases also had karyotyping results available. In three trisomy (T) 18 and three T13 cases, the Momguard results were concordant with the karyotyping results. For the T21 cases, except for one case belonging to the mid-risk zone, Momguard results from 23 out of 24 cases matched the karyotyping results. CONCLUSION: Momguard is a highly reliable screening tool for detecting T13, T18, and T21 cases in independent Korean cohort samples.
Aneuploidy ; Cohort Studies ; Down Syndrome ; Female ; Humans ; Informed Consent ; Karyotyping ; Mass Screening ; Pregnant Women ; Prenatal Diagnosis ; Trisomy

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Observed frequency of fetal trisomy between 16 and 24 gestational weeks in pregnant women older than 34 years at delivery.

Shin Ok JEONG ; You Jung HAN ; Si Won LEE ; Dong Wook KWAK ; Jin Hoon CHUNG ; Hyun Kyong AHN ; June Seek CHOI ; Jung Yeol HAN ; Moon Young KIM ; So Yeon PARK ; Hyun Mee RYU ; Min Hyoung KIM

Journal of Genetic Medicine.2015;12(2):92-95. doi:10.5734/JGM.2015.12.2.92

PURPOSE: Increased maternal age is a major risk factor for chromosomal abnormalities. The maternal age-specific risk of fetal trisomy was theoretically calculated. We investigated the actual frequency of fetal trisomy between 16 and 24 gestational weeks in pregnant women over the age of 34 at delivery. MATERIALS AND METHODS: We retrospectively, over a four-year period, reviewed the medical records of women with singleton pregnancies that started their antenatal care before the 10th week of pregnancy. Pregnant women aged 34 to 45 years at the time of delivery were enrolled and divided into groups of one-year intervals. We investigated the frequency of Down syndrome and all trisomies as a function of the maternal age and compared with the theoretical maternal-age-specific risk. RESULTS: Of the 5,858 pregnant women enrolled in the study, the rate of trisomy 21 was 0.29% (17 cases). The observed frequencies of trisomy 21 in women with maternal ages of 35 years and 40 years were 1:1,116 and 1:141, respectively. The rate of all trisomies was 0.39% (23 cases). The observed frequencies of all trisomies in women with maternal ages of 35 years and 40 years were 1:372 and 1:56, respectively. CONCLUSION: The frequencies of Down syndrome and all trisomies were proportional to the maternal age. However, the observed frequencies of Down syndrome and all trisomies between the 16 and 24 gestational weeks were lower than the theoretical rates.
Chromosome Aberrations ; Down Syndrome ; Epidemiology ; Female ; Humans ; Maternal Age ; Medical Records ; Pregnancy ; Pregnant Women* ; Retrospective Studies ; Risk Factors ; Trisomy*

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Noninvasive prenatal test for fetal chromosomal aneuploidies by massively parallel sequencing of cell-free fetal DNA in maternal plasma: The first clinical experience in Korea.

Sung Hee HAN ; Young Ho YANG ; Jae Song RYU ; Myung Soo KANG ; Young Jin KIM ; Kyoung Ryul LEE

Journal of Genetic Medicine.2015;12(2):85-91. doi:10.5734/JGM.2015.12.2.85

PURPOSE: Noninvasive prenatal test (NIPT) by massively parallel sequencing (MPS) of cell-free fetal DNA in maternal plasma marks a significant advancement in prenatal screening, minimizing the need for invasive testing of fetal chromosomal aneuploidies. Here, we report the initial clinical performance of NIPT in Korean pregnant women. MATERIALS AND METHODS: MPS-based NIPT was performed on 910 cases; 5 mL blood samples were collected and sequenced in the Shenzhen BGI Genomic Laboratory to identify aneuploidies. The risk of fetal aneuploidy was determined by L-score and t-score, and classified as high or low. The NIPT results were validated by karyotyping for the high-risk cases and neonatal follow-up for low-risk cases. RESULTS: NIPT was mainly requested for two clinical indications: abnormal biochemical serum-screening result (54.3%) and advanced maternal age (31.4%). Among 494 cases with abnormal biochemical serum-screening results, NIPT detected only 9 (1.8%) high-risk cases. Sixteen cases (1.8%) of 910 had a high risk for aneuploidy: 8 for trisomy 21, 2 for trisomy 18, 1 for trisomy 13, and 5 for sex chromosome abnormalities. Amniocentesis was performed for 7 of these cases (43.8%). In the karyotyping and neonatal data, no false positive or negative results were observed in our study. CONCLUSION: MPS-based NIPT detects fetal chromosomal aneuploidies with high accuracy. Introduction of NIPT as into clinical settings could prevent about 98% of unnecessary invasive diagnostic procedures.
Amniocentesis ; Aneuploidy* ; DNA* ; Down Syndrome ; Female ; Follow-Up Studies ; High-Throughput Nucleotide Sequencing* ; Humans ; Karyotyping ; Korea* ; Maternal Age ; Plasma* ; Pregnant Women ; Prenatal Diagnosis ; Sex Chromosome Aberrations ; Trisomy

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Validation of fetus aneuploidy in 221 Korean clinical samples using noninvasive chromosome examination: Clinical laboratory improvement amendments-certified noninvasive prenatal test.

Min Jeong KIM ; Chang Hyuk KWON ; Dong In KIM ; Hee Su IM ; Sungil PARK ; Ji Ho KIM ; Jin Sik BAE ; Myunghee LEE ; Min Seob LEE

Journal of Genetic Medicine.2015;12(2):79-84. doi:10.5734/JGM.2015.12.2.79

PURPOSE: We developed and validated a fetal trisomy detection method for use as a noninvasive prenatal test (NIPT) including a Clinical Laboratory Improvement Amendments (CLIA)-certified bioinformatics pipeline on a cloud-based computing system using both Illumina and Life Technology sequencing platforms for 221 Korean clinical samples. We determined the necessary proportions of the fetal fraction in the cell-free DNA (cfDNA) sample for NIPT of trisomies 13, 18, and 21 through a limit of quantification (LOQ) test. MATERIALS AND METHODS: Next-generation sequencing libraries from 221 clinical samples and three positive controls were generated using Illumina and Life Technology chemistries. Sequencing results were uploaded to a cloud and mapped on the human reference genome (GRCh37/hg19) using bioinformatics tools. Based on Z-scores calculated by normalization of the mapped read counts, final aneuploidy reports were automatically generated for fetal aneuploidy determination. RESULTS: We identified in total 29 aneuploid samples, and additional analytical methods performed to confirm the results showed that one of these was a false-positive. The LOQ test showed that the proportion of fetal fraction in the cfDNA sample would affect the interpretation of the aneuploidy results. CONCLUSION: Noninvasive chromosome examination (NICE), a CLIA-certified NIPT with a cloud-based bioinformatics platform, showed unambiguous success in fetus aneuploidy detection.
Aneuploidy* ; Computational Biology ; DNA ; Fetus* ; Genome ; High-Throughput Nucleotide Sequencing ; Humans ; Prenatal Diagnosis ; Trisomy

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Application of digital polymerase chain reaction technology for noninvasive prenatal test.

Seung Yong LEE ; Seung Yong HWANG

Journal of Genetic Medicine.2015;12(2):72-78. doi:10.5734/JGM.2015.12.2.72

Recently, noninvasive prenatal test (NIPT) has been adopted as a primary screening tool for fetal chromosomal aneuploidy. The principle of NIPT lies in isolating the fetal fraction of cell-free DNA in maternal plasma and analyzing it with bioinformatic tools to measure the amount of gene from the target chromosome, such as chromosomes 21, 18, and 13. NIPT will contribute to decreasing the need for unnecessary invasive procedures, including amniocentesis and chorionic villi sampling, for confirming fetal aneuploidy because of its higher positive predictive value than that of the conventional prenatal screening method. However, its greater cost than that of the current antenatal screening protocol may be an obstacle to the adoption of this innovative technique in clinical practice. Digital polymerase chain reaction (dPCR) is a novel approach for detecting and quantifying nucleic acid. dPCR provides real-time diagnostic advantages with higher sensitivity, accuracy, and absolute quantification than conventional quantitative PCR. Since the groundbreaking discovery that fetal cell-free nucleic acid exists in maternal plasma was reported, dPCR has been used for the quantification of fetal DNA and for screening for fetal aneuploidy. It has been suggested that dPCR will decrease the cost by targeting specific sequences in the target chromosome, and dPCR-based noninvasive testing will facilitate progress toward the implementation of a noninvasive approach for screening for trisomy 21, 18, and 13. In this review, we highlight the principle of dPCR and discuss its future implications in clinical practice.
Amniocentesis ; Aneuploidy ; Chorionic Villi Sampling ; Chromosome Aberrations ; DNA ; Down Syndrome ; Female ; Mass Screening ; Plasma ; Polymerase Chain Reaction* ; Pregnancy ; Prenatal Diagnosis

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Advantages of the single nucleotide polymorphism-based noninvasive prenatal test.

Kunwoo KIM

Journal of Genetic Medicine.2015;12(2):66-71. doi:10.5734/JGM.2015.12.2.66

Down syndrome screening with cell-free DNA (cfDNA) in the maternal plasma has recently received much attention in the prenatal diagnostic field. Indeed, a large amount of evidence has already accumulated to show that screening tests with cfDNA are more sensitive and specific than conventional maternal serum and/or ultrasound screening. Globally, more than 1,000,000 of these noninvasive prenatal tests (NIPTs) have been performed to date. There are several different methods for NIPTs that are currently commercially available, including shotgun massively parallel sequencing, targeted massively parallel sequencing, and single nucleotide polymorphism (SNP)-based methods. All of these methods have their own advantages and disadvantages. In this review, I will focus specifically on the SNP-based NIPT.
DNA ; Down Syndrome ; High-Throughput Nucleotide Sequencing ; Mass Screening ; Plasma ; Polymorphism, Single Nucleotide ; Prenatal Diagnosis ; Ultrasonography

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