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Ting T.W.,Genetics Service | Ting T.W.,National University of Singapore | Jamuar S.S.,Genetics Service | Jamuar S.S.,National University of Singapore | And 11 more authors.
Pediatric Cardiology

Left ventricular non-compaction (LVNC) is reported to affect 0.14 % of the pediatric population. The etiology is heterogeneous and includes a wide number of genetic causes. As an illustration, we report two patients with LVNC who were diagnosed with a genetic syndrome. We then review the literature and suggest a diagnostic algorithm to evaluate individuals with LVNC. Case 1 is a 15-month-old girl who presented with hypotonia, global developmental delay, congenital heart defect (including LVNC) and facial dysmorphism. Case 2 is a 7-month-old girl with hypotonia, seizures, laryngomalacia and LVNC. We performed chromosomal microarray for both our patients and detected chromosome 1p36 microdeletion. We reviewed the literature for other genetic causes of LVNC and formulated a diagnostic algorithm, which includes assessment for syndromic disorders, inborn error of metabolism, copy number variants and non-syndromic monogenic disorder associated with LVNC. LVNC is a relatively newly recognized entity, with heterogeneity in underlying etiology. For a systematic approach of evaluating the underlying cause to improve clinical care of these patients, a diagnostic algorithm for genetic evaluation of patients with LVNC is proposed. © 2015, Springer Science+Business Media New York. Source

Ho S.S.Y.,National University Hospital Singapore | Huan P.T.,National University Hospital Singapore | Leow G.H.,National University Hospital Singapore | Ching L.K.,DNA Diagnostic and Research Laboratory | And 4 more authors.
Prenatal Diagnosis

Objective: Current methods of prenatal diagnosis to detect beta-thalassemia are Sanger sequencing and reverse dot blot. These methods are time-consuming and can prolong assay turnaround time. We aim to develop a sensitive and rapid method to detect 27 beta-thalassemia mutations using pyrosequencing. Method: Pyrosequencing primer pairs and sequencing primers were designed to detect 27 most common beta-thalassemia mutations found in Singapore. Pyrosequencing was performed on 191 DNA samples with known beta-thalassemia mutations isolated from 143 peripheral blood and 48 prenatal samples (seven chorionic villus biopsies, 26 cultured amniocytes, 15 uncultured amniocytes). All mutations were validated with Sanger sequencing. Results: Pyrosequencing identified 210 alleles with beta-thalassemia mutations and 82 alleles without mutations with 100% sensitivity (lower 95% confidence interval [CI], 97.8%) and 100% specificity (lower 95% CI, 94.4%). All pyrosequences were concordant with Sanger-based sequences. Pyrosequencing was able to detect DNA concentrations as low as 2ng, obviating the need for cell culture in volume-restricted samples. Sample receipt-to-report assay turnaround times were 16 to 18h (Sanger sequencing) and 4 to 6h (pyrosequencing). Conclusion: Pyrosequencing is a rapid and sensitive method to detect common beta-thalassemia mutations without the need for cell culture, thus reducing the assay turnaround time. What's already known about this topic? The most common prenatal diagnostic methods to detect beta-thalassemia mutations are Sanger sequencing and reverse dot blot. Large amounts of DNA are required, and AF culture is usually necessary. This prolongs the assay turnaround time. What does this study add? This study describes the utilization of pyrosequencing to detect beta-thalassemia mutations in AF samples without cell culture. This reduces the assay turnaround time. © 2013 John Wiley & Sons, Ltd. Source

Liu X.,National University of Singapore | Law H.Y.,DNA Diagnostic and Research Laboratory | Tan Y.M.,DNA Diagnostic and Research Laboratory | Hong Y.,National University of Singapore
Analytical Biochemistry

Based on a novel Q-primer real-time polymerase chain reaction (PCR) system, we designed allele-specific Q-primers for the detection of three β-thalassemia mutations [Cd41/42(-TCTT), IVSI nt5 (G>C), and IVSII nt654 (C>T)] that have a high carrier frequency in Southeast Asia. With clear distinction between heterozygote and wild-type, ΔCt (threshold cycle) values were defined. The results of evaluating 139 blinded samples by our system match perfectly with those obtained by the conventional reverse dot blot (RDB) method. With a 384-well plate that included replicates in the same analysis, our throughput reached 190 reactions per run with a turnaround time as short as 130min, and the cost of consumables was as low as 1 (US) for each test. © 2010 Elsevier Inc. Source

Chan M.,National Cancer Center | Ji S.M.,National Cancer Center | Liaw C.S.,National Cancer Center | Yap Y.S.,National Cancer Center | And 15 more authors.
Breast Cancer Research and Treatment

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles. © 2012 Springer Science+Business Media, LLC. Source

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