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  1. Fulltext Comparison of the ABC and ACMG systems for variant classification
    Houge G, Bratland E, Aukrust I, Tveten K, Žukauskaitė G, Sansovic I, et al.
    Eur J Hum Genet, 2024 Jul;32(7):858-863.
    PMID: 38778080 DOI: 10.1038/s41431-024-01617-8
    The ABC and ACMG variant classification systems were compared by asking mainly European clinical laboratories to classify variants in 10 challenging cases using both systems, and to state if the variant in question would be reported as a relevant result or not as a measure of clinical utility. In contrast to the ABC system, the ACMG system was not made to guide variant reporting but to determine the likelihood of pathogenicity. Nevertheless, this comparison is justified since the ACMG class determines variant reporting in many laboratories. Forty-three laboratories participated in the survey. In seven cases, the classification system used did not influence the reporting likelihood when variants labeled as "maybe report" after ACMG-based classification were included. In three cases of population frequent but disease-associated variants, there was a difference in favor of reporting after ABC classification. A possible reason is that ABC step C (standard variant comments) allows a variant to be reported in one clinical setting but not another, e.g., based on Bayesian-based likelihood calculation of clinical relevance. Finally, the selection of ACMG criteria was compared between 36 laboratories. When excluding criteria used by less than four laboratories (<10%), the average concordance rate was 46%. Taken together, ABC-based classification is more clear-cut than ACMG-based classification since molecular and clinical information is handled separately, and variant reporting can be adapted to the clinical question and phenotype. Furthermore, variants do not get a clinically inappropriate label, like pathogenic when not pathogenic in a clinical context, or variant of unknown significance when the significance is known.
    Matched MeSH terms: Genetic Testing/methods
  2. [Simple and rapid analysis of beta-thalassemia mutation by sequence-specific amplification]
    Harano K, Harano T
    Rinsho Byori, 2013 Mar;61(3):217-23.
    PMID: 23785790
    This study was done to detect and diagnose beta-thalassemia (beta-Thal) gene quickly. We applied sequence specific Amplification (SSA) method to the analysis. 13 kinds of beta-Thal and two kinds of hemoglobin variants were able to detect under the same PCR condition. These mutations were found frequently in ten countries of Asian region (the southern part of China, Vietnam, Cambodia, Thailand, Myanmar, Malaysia, Singapore, Indonesia, Pakistan, India), and 15 kinds in total (-28CapA-->G, CD5-CT, CD8/9+-G, CD15G-->A, CD17A-->T, IVSI-1G-->T, CD41/42-4del, CD16-C, CD26G-->A(betaE), IVSI-5G-->C, CD35C-->A, CD71/72 +A, CD6A-->T (betaS), -619del, IVSII-654C-->T). More than 80% of patients are included in these mutations. To make the reagents a kit, the procedure became simple and rapid. DNA was extracted by salting out method. The PCR product was detected by polyacrylamide gel electrophoresis and silver staining. The confirmation of the variant was done by the PCR-direct sequencing method. It took approximately six hours for PCR reaction, electrophoresis and staining. This method made us to detect and diagnose beta-Thal in one day.
    Matched MeSH terms: Genetic Testing/methods
  3. Impact of BRCA1/2 cascade testing on anxiety, depression, and cancer worry levels among unaffected relatives in a multiethnic Asian cohort
    Padmanabhan H, Mariapun S, Lee SY, Hassan NT, Lee DS, Meiser B, et al.
    J Genet Couns, 2023 Feb;32(1):43-56.
    PMID: 35913122 DOI: 10.1002/jgc4.1619
    Cascade testing for families with BRCA pathogenic variants is important to identify relatives who are carriers. These relatives can benefit from appropriate risk management and preventative strategies arising from an inherited increased risk of breast, ovarian, prostate, melanoma, and pancreatic cancers. Cascade testing has the potential to enable cost-effective cancer control even in low- and middle-income settings, but few studies have hitherto evaluated the psychosocial impact of cascade testing in an Asian population, where the cultural and religious beliefs around inheritance and destiny have previously been shown to influence perception and attitudes toward screening. In this study, we evaluated the short- and long-term psychosocial impact of genetic testing among unaffected relatives of probands identified through the Malaysian Breast Cancer Genetics Study and the Malaysian Ovarian Cancer Study, using validated questionnaires (Hospital Anxiety and Depression Scale and Cancer Worry Scale) administered at baseline, and 1-month and 2-year post-disclosure of results. Of the 305 unaffected relatives from 98 independent families who were offered cascade testing, 256 (84%) completed predictive testing and family history of cancers was the only factor significantly associated with uptake of predictive testing. We found that the levels of anxiety, depression, and cancer worry among unaffected relatives decreased significantly after result disclosure and remained low 2-year post-result disclosure. Younger relatives and relatives of Malay descent had higher cancer worry at both baseline and after result disclosure compared to those of Chinese and Indian descent, whereas relatives of Indian descent and those with family history of cancers had higher anxiety and depression levels post-result disclosure. Taken together, the results from this Asian cohort highlight the differences in psychosocial needs in different communities and inform the development of culture-specific genetic counseling strategies.
    Matched MeSH terms: Genetic Testing/methods
  4. Fulltext A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2
    Zanti M, O'Mahony DG, Parsons MT, Li H, Dennis J, Aittomäkkiki K, et al.
    Hum Mutat, 2023;2023.
    PMID: 38725546 DOI: 10.1155/2023/9961341
    A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.
    Matched MeSH terms: Genetic Testing/methods
  5. Fulltext Prenatal diagnosis of aneuploidies in amniotic fluid by multiple ligation-dependent probe amplification (MLPA) analysis
    Hamidah NH, Munirah AR, Hafiza A, Farisah AR, Shuhaila A, Norzilawati MN, et al.
    Malays J Pathol, 2014 Dec;36(3):163-8.
    PMID: 25500514 MyJurnal
    Prenatal diagnosis is essential in the new era of diagnosis and management of genetic diseases in obstetrics. Multiple ligation-dependent probe amplification (MLPA) is a recent technique for prenatal diagnosis for the relative quantification of 40 different nucleic acid sequences in one single reaction. We had utilized the MLPA technique in detecting aneuploidies in amniotic fluid samples from 25 pregnant women from the Obstetrics and Gynaecology Department UKMMC, versus the quantitative fluorescent polymerase chain reaction (QF-PCR) method. Conclusive results were obtained in 18 cases and all were concordant with that of the QF-PCR. All four cases of trisomies were correctly identified including one case with maternal cell contamination.
    Matched MeSH terms: Genetic Testing/methods*
  6. Fulltext α-Thalassemia with Haemoglobin Adana mutation: prenatal diagnosis
    Zainal NZ, Alauddin H, Ahmad S, Hussin NH
    Malays J Pathol, 2014 Dec;36(3):207-11.
    PMID: 25500521
    Thalassaemia carriers are common in the Asian region including Malaysia. Asymptomatic patients can be undiagnosed until they present for their antenatal visits. Devastating obstetric outcome may further complicate the pregnancy if both parents are thalassaemia carriers leading to hydrophic fetus due to haemoglobin Bart's disease. However in certain cases where unexplained hydrops fetalis occur in parents with heterozygous thalassaemia carrier,mutated α genes should be suspected. We report a twenty-nine year old woman in her third pregnancy with two previous pregnancies complicated by early neonatal death at 21 and 28 weeks of gestation due to hydrops fetalis. DNA analysis revealed the patient to have heterozygous (--SEA) α-gene deletion, while her husband has a compound heterozygosity for α(3.7) deletion and codon 59 (GGC → GAC) mutation of the α-gene. This mutation, also known as hemoglobin Adana, can explain hydrops fetalis resulting from two alpha gene deletions from the patient (mother) and a single alpha gene deletion with mutation from the father. The third pregnancy resulted in a grossly normal baby boy with 3 α-gene deletions (HbH disease). We postulate that, in view of heterogenisity of the α-thalassaemia in this patient with severely unstable haemoglobin Adana chains from her husband, there will be a 25% possibility of fetal hydrops in every pregnancy.
    Matched MeSH terms: Genetic Testing/methods*
  7. Fulltext Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions
    Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, et al.
    Epilepsia, 2014 Apr;55(4):496-506.
    PMID: 24597466 DOI: 10.1111/epi.12564
    To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?
    Matched MeSH terms: Genetic Testing/methods*
  8. Fulltext Permissibility of prenatal diagnosis and abortion for fetuses with severe genetic disorder: type 1 spinal muscular atrophy
    Sasongko TH, Salmi AR, Zilfalil BA, Albar MA, Mohd Hussin ZA
    Ann Saudi Med, 2010 Nov-Dec;30(6):427-31.
    PMID: 21060155 DOI: 10.4103/0256-4947.72259
    Abortion has been largely avoided in Muslim communities. However, Islamic jurists have established rigorous parameters enabling abortion of fetuses with severe congenital abnormalities. This decision-making process has been hindered by an inability to predict the severity of such prenatally-diagnosed conditions, especially in genetic disorders with clinical heterogeneity, such as spinal muscular atrophy (SMA). Heterogeneous phenotypes of SMA range from extremely severe type 1 to very mild type 4. Advances in molecular genetics have made it possible to perform prenatal diagnosis and to predict the types of SMA with its potential subsequent severity. Such techniques will make it possible for clinicians working in predominantly Muslim countries to counsel their patients accurately and in harmony with their religious beliefs. In this paper, we discuss and postulate that with our current knowledge of determining SMA types and severity with great accuracy, abortion is legally applicable for type 1 SMA.
    Matched MeSH terms: Genetic Testing/methods*
  9. Fulltext Metabolic and genetic screening of electromagnetic hypersensitive subjects as a feasible tool for diagnostics and intervention
    De Luca C, Thai JC, Raskovic D, Cesareo E, Caccamo D, Trukhanov A, et al.
    Mediators Inflamm, 2014;2014:924184.
    PMID: 24812443 DOI: 10.1155/2014/924184
    Growing numbers of "electromagnetic hypersensitive" (EHS) people worldwide self-report severely disabling, multiorgan, non-specific symptoms when exposed to low-dose electromagnetic radiations, often associated with symptoms of multiple chemical sensitivity (MCS) and/or other environmental "sensitivity-related illnesses" (SRI). This cluster of chronic inflammatory disorders still lacks validated pathogenetic mechanism, diagnostic biomarkers, and management guidelines. We hypothesized that SRI, not being merely psychogenic, may share organic determinants of impaired detoxification of common physic-chemical stressors. Based on our previous MCS studies, we tested a panel of 12 metabolic blood redox-related parameters and of selected drug-metabolizing-enzyme gene polymorphisms, on 153 EHS, 147 MCS, and 132 control Italians, confirming MCS altered (P < 0.05-0.0001) glutathione-(GSH), GSH-peroxidase/S-transferase, and catalase erythrocyte activities. We first described comparable-though milder-metabolic pro-oxidant/proinflammatory alterations in EHS with distinctively increased plasma coenzyme-Q10 oxidation ratio. Severe depletion of erythrocyte membrane polyunsaturated fatty acids with increased ω 6/ ω 3 ratio was confirmed in MCS, but not in EHS. We also identified significantly (P = 0.003) altered distribution-versus-control of the CYP2C19∗1/∗2 SNP variants in EHS, and a 9.7-fold increased risk (OR: 95% C.I. = 1.3-74.5) of developing EHS for the haplotype (null)GSTT1 + (null)GSTM1 variants. Altogether, results on MCS and EHS strengthen our proposal to adopt this blood metabolic/genetic biomarkers' panel as suitable diagnostic tool for SRI.
    Matched MeSH terms: Genetic Testing/methods*
  10. Fulltext Genetic analyses favour an ancient and natural origin of elephants on Borneo
    Sharma R, Goossens B, Heller R, Rasteiro R, Othman N, Bruford MW, et al.
    Sci Rep, 2018 01 17;8(1):880.
    PMID: 29343863 DOI: 10.1038/s41598-017-17042-5
    The origin of the elephant on the island of Borneo remains elusive. Research has suggested two alternative hypotheses: the Bornean elephant stems either from a recent introduction in the 17th century or from an ancient colonization several hundreds of thousands years ago. Lack of elephant fossils has been interpreted as evidence for a very recent introduction, whereas mtDNA divergence from other Asian elephants has been argued to favor an ancient colonization. We investigated the demographic history of Bornean elephants using full-likelihood and approximate Bayesian computation analyses. Our results are at odds with both the recent and ancient colonization hypotheses, and favour a third intermediate scenario. We find that genetic data favour a scenario in which Bornean elephants experienced a bottleneck during the last glacial period, possibly as a consequence of the colonization of Borneo, and from which it has slowly recovered since. Altogether the data support a natural colonization of Bornean elephants at a time when large terrestrial mammals could colonise from the Sunda shelf when sea levels were much lower. Our results are important not only in understanding the unique history of the colonization of Borneo by elephants, but also for their long-term conservation.
    Matched MeSH terms: Genetic Testing/methods
  11. Fulltext Genetic analysis and selection of Bambara groundnut (Vigna subterranea [L.] Verdc.) landraces for high yield revealed by qualitative and quantitative traits
    Khan MMH, Rafii MY, Ramlee SI, Jusoh M, Al Mamun M
    Sci Rep, 2021 Apr 07;11(1):7597.
    PMID: 33828137 DOI: 10.1038/s41598-021-87039-8
    As a crop for the new millennium Bambara groundnut (Vigna subterranea [L.] Verdc.) considered as leading legumes in the tropical regions due to its versatile advantages. The main intent of this study was to find out the high yielding potential genotypes and considering these genotypes to develop pure lines for commercial cultivation in Malaysia. Considering the 14 qualitative and 27 quantitative traits of fifteen landraces the variation and genetic parameters namely, variability, heritability, genetic advance, characters association, and cluster matrix were determined. ANOVA revealed significant variation for all the agronomic traits (except plant height). Among the accessions, highly significant differences (P ≤ 0.01) were found for almost all the traits excluding fifty percent flowering date, seed length, seed width. The 16 traits out of the 27 quantitative traits had a coefficient of variation (CV) ≥ 20%. A positive and intermediate to perfect highly significant association (r = 0.23 to 1.00; P 
    Matched MeSH terms: Genetic Testing/methods
  12. Pilot study of the sensitivity and specificity of the DNA integrity assay for stool-based detection of colorectal cancer in Malaysian patients
    Yehya AH, Yusoff NM, Khalid IA, Mahsin H, Razali RA, Azlina F, et al.
    Asian Pac J Cancer Prev, 2012;13(5):1869-72.
    PMID: 22901138
    BACKGROUND: To assess the diagnostic potential of tumor-associated high molecular weight DNA in stool samples of 32 colorectal cancer (CRC) patients compared to 32 healthy Malaysian volunteers by means of polymerase chain reaction (PCR).

    METHODS: Stool DNA was isolated and tumor-associated high molecular weight DNA (1.476 kb fragment including exons 6-9 of the p53 gene) was amplified using PCR and visualized on ethidium bromide-stained agarose gels.

    RESULTS: Out of 32 CRC patients, 18 were positive for the presence of high molecular weight DNA as compared to none of the healthy individuals, resulting in an overall sensitivity of 56.3% with 100% specificity. Out of 32 patients, 23 had tumor on the left side and 9 on the right side, 16 and 2 being respectively positive. This showed that high molecular weight DNA was significantly (p=0.022) more detectable in patients with left side tumor (69.6% vs 22.2%). Out of 32 patients, 22 had tumors larger than 1.0 cm, 18 of these (81.8%) being positive for long DNA as compared to not a single patient with tumor size smaller than 1.0 cm (p<0.001).

    CONCLUSION: We detected CRC-related high molecular weight p53 DNA in stool samples of CRC patients with an overall sensitivity of 56.3% with 100% specificity, with a strong tumor size dependence.

    Matched MeSH terms: Genetic Testing/methods*
  13. Pharmacogenetic screening of carbamazepine-induced severe cutaneous allergic reactions
    Locharernkul C, Shotelersuk V, Hirankarn N
    J Clin Neurosci, 2011 Oct;18(10):1289-94.
    PMID: 21802305 DOI: 10.1016/j.jocn.2010.12.054
    Recent studies associated the HLA-B 1502 allele with carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients from China, Thailand and Malaysia. No association has been found in patients from Europe or Japan. Linkage summary reports from East and South-east Asia predict a highly significant odds ratio (OR) of 84.75 (95% confidence interval [CI]=42.53-168.91; p=8.96×10[-15]) with sensitivity and negative predictive values of 92% and 98%, respectively. The higher prevalence of HLA-B 1502 allele among certain Asian populations (10-15%) compared to Caucasians (1-2%) may explain a 10-fold to 25-fold higher incidence of CBZ-SJS/TEN in patients from Asia. Screening for HLA-B 1502 before using CBZ can prevent SJS/TEN in certain populations, but screening may be less beneficial in populations with low HLA-B 1502 allele frequency and in patients exposed to CBZ for more than 2 months. A retrospective study demonstrated that the costs of HLA-B 1502 screening were less than those of SJS treatment. This article reviews possible benefits and concerns of HLA-B 1502 screening in clinical practice.
    Matched MeSH terms: Genetic Testing/methods*
  14. Screening for gap junction protein beta-2 gene mutations in Malays with autosomal recessive, non-syndromic hearing loss, using denaturing high performance liquid chromatography
    Aishah ZS, Khairi MD, Normastura AR, Zafarina Z, Zilfalil BA
    J Laryngol Otol, 2008 Dec;122(12):1284-8.
    PMID: 18353197 DOI: 10.1017/S0022215108002041
    To determine the frequency and type of gap junction protein beta-2 gene mutations in Malay patients with autosomal recessive, non-syndromic hearing loss.
    Matched MeSH terms: Genetic Testing/methods
  15. Fulltext Use of the denaturing gradient gel electrophoresis (DGGE) method for mutational screening of patients with familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB)
    Azian M, Hapizah MN, Khalid BA, Khalid Y, Rosli A, Jamal R
    Malays J Pathol, 2006 Jun;28(1):7-15.
    PMID: 17694954 MyJurnal
    Familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB) are autosomal dominant inherited diseases of lipid metabolism caused by mutations in the low density lipoprotein (LDL) receptor and apolipoprotein B 100 genes. FH is clinically characterised by elevated concentrations of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), presence of xanthomata and premature atherosclerosis. Both conditions are associated with coronary artery disease but may be clinically indistinguishable. Seventy-two (72) FH patients were diagnosed based on the Simon Broome's criteria. Mutational screening was performed by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). Positive mutations were subjected to DNA sequencing for confirmation of the mutation. We successfully amplified all exons in the LDL receptor and apo B100 genes. DGGE was performed in all exons of the LDL receptor (except for exons 4-3', 18 and promoter region) and apo B100 genes. We have identified four different mutations in the LDL receptor gene but no mutation was detected in the apo B 100 gene. The apo B100 gene mutation was not detected on DGGE screening as sequencing was not performed for negative cases on DGGE technique. To our knowledge, the C234S mutation (exon 5) is a novel mutation worldwide. The D69N mutation (exon 3) has been reported locally while the R385W (exon 9) and R716G (exon 15) mutations have not been reported locally. However, only 4 mutations have been identified among 14/72 patients (19.4%) in 39 FH families. Specificity (1-false positive) of this technique was 44.7% based on the fact that 42/76 (55.3%) samples with band shifts showed normal DNA sequencing results. A more sensitive method needs to be addressed in future studies in order to fully characterise the LDLR and apo B100 genes such as denaturing high performance liquid chromatography. In conclusion, we have developed the DNA analysis for FH patients using PCR-DGGE technique. DNA analysis plays an important role to characterise the type of mutations and forms an adjunct to clinical diagnosis.
    Matched MeSH terms: Genetic Testing/methods*
  16. Fulltext Screening of concurrent alpha-thalassaemia 1 in beta-thalassaemia carriers
    Chong YM, Tan JA, Zubaidah Z, Rahimah A, Kuldip K, George E
    Med J Malaysia, 2006 Jun;61(2):217-20.
    PMID: 16898315
    Thalassaemia is an inherited blood disorder and is a significant public health problem in Malaysia, with many not knowing they carry the gene for thalassaemia. The two major forms are alpha and beta thalassaemia. An individual can co-inherit both the alpha and beta thalassaemia genes. This study determined the frequency of concurrent carriers of alpha thalassaemia in 231 beta thalassaemia carriers. Gap-PCR was done on extracted DNA of the beta thalassaemia samples to check for alpha thalassaemia 1 molecular defect. Eight (3.5%) samples were found to have concurrently inherited the alpha thalassaemia 1 (- -SEA) deletion. The significant carrier rate for alpha thalassaemia 1 indicates the need for the implementation of DNA analysis to complement thalassaemia screening in high risk populations.
    Matched MeSH terms: Genetic Testing/methods*
  17. Anion exchanger 1 mutations associated with distal renal tubular acidosis in the Thai population
    Yenchitsomanus PT, Sawasdee N, Paemanee A, Keskanokwong T, Vasuvattakul S, Bejrachandra S, et al.
    J Hum Genet, 2003;48(9):451-456.
    PMID: 12938018 DOI: 10.1007/s10038-003-0059-6
    We have previously demonstrated that compound heterozygous (SAO/G701D) and homozygous (G701D/G701D) mutations of the anion exchanger 1 (AE1) gene, encoding erythroid and kidney AE1 proteins, cause autosomal recessive distal renal tubular acidosis (AR dRTA) in Thai patients. It is thus of interest to examine the prevalence of these mutations in the Thai population. The SAO and G701D mutations were examined in 844 individuals from north, northeast, central, and south Thailand. Other reported mutations including R602H, DeltaV850, and A858D were also examined in some groups of subjects. The SAO mutation was common in the southern Thai population; its heterozygote frequency was 7/206 and estimated allele frequency 1.70%. However, this mutation was not observed in populations of three other regions of Thailand. In contrast, the G701D mutation was not found in the southern population but was observed in the northern, northeastern, and central populations, with heterozygote frequencies of 1/216, 3/205, and 1/217, and estimated allele frequencies of 0.23%, 0.73%, and 0.23%, respectively. The higher allele frequency of the G701D mutation in the northeastern Thai population corresponds to our previous finding that all Thai patients with AR dRTA attributable to homozygous G701D mutation originate from this population. This suggests that the G701D allele that is observed in this region might arise in northeastern Thailand. The presence of patients with compound heterozygous SAO/G701D in southern Thailand and Malaysia and their apparently absence in northeastern Thailand indicate that the G701D allele may have migrated to the southern peninsular region where SAO is common, resulting in pathogenic allelic interaction.
    Matched MeSH terms: Genetic Testing/methods
  18. Fulltext Semiquantitative screening test for G6PD deficiency detects severe deficiency but misses a substantial proportion of partially-deficient females
    Ainoon O, Alawiyah A, Yu YH, Cheong SK, Hamidah NH, Boo NY, et al.
    Southeast Asian J. Trop. Med. Public Health, 2003 Jun;34(2):405-14.
    PMID: 12971572
    Neonatal screening for G6PD deficiency has long been established in many countries. The aim of the study was to determine whether the routine semiquantitative fluorescent spot test could detect all cases of G6PD deficiency, including those cases with partial deficiency (residual red cell G6PD activity between 20-60% of normal). We compared the results of G6PD screening by the semiquantitative fluorescent spot test and quantitative G6PD activity assay on a group of 976 neonates and 67 known female heterozygotes. The values for mean G6PD activity of G6PD-normal neonates and 293 healthy adult females were determined. There was no significant difference in the mean normal G6PD activity between the two racial groups in the neonates (669 Malays, 307 Chinese) and in the 293 healthy adult females (150 Malays, 143 Chinese) group. The values for the upper limits of total deficiency (20% of normal residual activity) for neonates and adult females were 2.92 U/gHb and 1.54 U/gHb, respectively. The upper limits of partial deficiency (60% of normal residual activity) were 8.7 U/gHb and 4.6 U/gHb respectively. The prevalence of G6PD deficiency among the male neonates was 5.1% (26) by both the fluorescent spot test and the enzyme assay method. The G6PD activity levels of all 26 cases of G6PD-deficient male neonates were < 20% normal (severe enzyme deficiency). In the female neonate group, the frequency of G6PD deficiency was 1.3% (6 of 472) by the fluorescent spot test and 9.35% (44 of 472) by enzyme assay. The 6 cases diagnosed as deficient by the fluorescent spot test showed severe enzyme deficiency (< 2.92 U/gHb). The remaining 38 female neonates had partial enzyme deficiency and all were misdiagnosed as normal by the fluorescent spot test. In the female heterozygote group, G6PD deficiency was diagnosed in 53% (35 of 67) by enzyme assay and in 7.5% (4 of 67) of cases by the fluorescent spot test. The 4 cases detected by fluorescent spot test had severe enzyme deficiency (<1.6 U/gHb). The remaining 31 (46.3%) cases, diagnosed as normal by fluorescent spot test, showed partial G6PD deficiency. In conclusion, we found that the semiquantitative fluorescent spot test could only diagnose cases of total G6PD deficiency and misclassified the partially-deficient cases as normal. In this study, the overall prevalence of G6PD deficiency was 3.28% by the semiquantitative fluorescent spot test and 7.17% by enzyme assay. This means that 3.9% of G6PD-deficient neonates were missed by the routine fluorescent spot test and they were found to be exclusively females. This study demonstrates a need to use a method that can correctly classify female heterozygotes with partial G6PD deficiency. The clinical implication is that these individuals may be at risk of the hemolytic complication of G6PD deficiency.
    Matched MeSH terms: Genetic Testing/methods
  19. Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations
    Choong SS, Latiff ZA, Mohamed M, Lim LL, Chen KS, Vengidasan L, et al.
    Clin Genet, 2012 Dec;82(6):564-8.
    PMID: 22233476 DOI: 10.1111/j.1399-0004.2012.01841.x
    Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant disorder where affected individuals carry a 50% risk of developing cancer before 30 years of age. It is most commonly associated with mutations in the tumour suppressor gene, TP53. Adrenocortical carcinoma (ACC) is a very rare paediatric cancer, and up to 80% of affected children are found to carry germline TP53 mutations. Hence, we propose using childhood ACC incidence as selection criteria for referral for TP53 mutation testing, independent of familial cancer history. Under the auspices of the Malaysian Society of Paediatric Haematology-Oncology, four eligible children diagnosed with ACC over a 30-month study period were referred for mutation testing. Three had a germline TP53 mutation. Subsequent TP53 testing in relatives showed two inherited mutations and one de novo mutation. These findings strongly support paediatric ACC as a useful sentinel cancer for initiating a germline TP53/LFS detection programme, particularly in countries where the lack of structured oncogenetic practice precludes the identification of families with LFS features.
    Matched MeSH terms: Genetic Testing/methods*
  20. Fulltext Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder
    Maier R, Moser G, Chen GB, Ripke S, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Coryell W, et al.
    Am J Hum Genet, 2015 Feb 05;96(2):283-94.
    PMID: 25640677 DOI: 10.1016/j.ajhg.2014.12.006
    Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.
    Matched MeSH terms: Genetic Testing/methods
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