Publications by authors named "Bin Alwi Zilfalil"

47 Publications

Prevalence and distribution of major β-thalassemia mutations and HbE/β-thalassemia variant in Nepalese ethnic groups.

Hematol Oncol Stem Cell Ther 2021 Feb 11. Epub 2021 Feb 11.

Malaysian Node of Human Variome Project, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia; Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia. Electronic address:

Background: Beta-thalassemia is a genetic disorder that is inherited in an autosomal recessive pattern. This genetic disease leads to a defective beta-globin hemoglobin chain causing partial or complete beta-globin chain synthesis loss. Beta-thalassemia major patients need a continuous blood transfusion and iron chelation to maintain the normal homeostasis of red blood cells (RBCs) and other systems in the body. Patients also require treatment procedures that are costly and tedious, resulting in a serious health burden for developing nations such as Nepal.

Methods: A total of 61 individuals clinically diagnosed to have thalassemia were genotyped with multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Twenty-one major mutations were investigated using allele-specific primers grouped into six different panels.

Results: The most common mutations found (23%) were IVS 1-5 (G-C) and Cd 26 (G-A) (HbE), followed by 619 deletion, Cd 8/9 (+G), Cd 16 (-C), Cd 41/42 (-TTCT), IVS 1-1 (G-T), Cd 19 (A-G), and Cd 17 (A-T) at 20%, 12%, 8%, 6%, 4%, 3%, and 1%, respectively.

Conclusion: The results of this study revealed that Nepal's mutational profile is comparable to that of its neighboring countries, such as India and Myanmar. This study also showed that thalassemia could be detected across 17 Nepal's ethnic groups, especially those whose ancestors originated from India and Central Asia.
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http://dx.doi.org/10.1016/j.hemonc.2021.01.004DOI Listing
February 2021

Genotype-Phenotype Correlation of β-Thalassemia in Malaysian Population: Toward Effective Genetic Counseling.

Hemoglobin 2020 May 26;44(3):184-189. Epub 2020 Jun 26.

Thalassaemia Research Centre, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand.

Effective prevention of β-thalassemia (β-thal) requires strategies to detect at-risk couples. This is the first study attempting to assess the prevalence of silent β-thal carriers in the Malaysian population. Hematological and clinical parameters were evaluated in healthy blood donors and patients with β-thal trait, Hb E (: c.79G>A)/β-thal and β-thal major (β-TM). β-Globin gene sequencing was carried out for 52 healthy blood donors, 48 patients with Hb E/β-thal, 34 patients with β-TM and 38 patients with β-thal trait. The prevalence of silent β-thal carrier phenotypes found in 25.0% of healthy Malaysian blood donors indicates the need for clinician's awareness of this type in evaluating β-thal in Malaysia. Patients with β-TM present at a significantly younger age at initial diagnosis and require more blood transfusions compared to those with Hb E/β-thal. The time at which genomic DNA was extracted after blood collection, particularly from patients with β-TM and Hb E/β-thal, was found to be an important determinant of the quality of the results of the β-globin sequencing. Public education and communication campaigns are recommended as apparently healthy individuals have few or no symptoms and normal or borderline hematological parameters. β-Globin gene mutation characterization and screening for silent β-thal carriers in regions prevalent with β-thal are recommended to develop more effective genetic counseling and management of β-thal.
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http://dx.doi.org/10.1080/03630269.2020.1781652DOI Listing
May 2020

Genetic polymorphisms of HbE/beta thalassemia related to clinical presentation: implications for clinical diversity.

Ann Hematol 2020 Apr 20;99(4):729-735. Epub 2020 Feb 20.

Department Hematology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

HbE/Beta thalassemia (HbE/β-thalassemia) is one of the common genetic disorders in South East Asia. It is heterogeneous in its clinical presentation and molecular defects. There are genetic modifiers which have been reported to influence the disease severity of this disorder. The aim of this study was to determine the genetic polymorphisms which were responsible for the disease clinical diversity. A case-control study was conducted among Malay transfusion-dependent HbE/β-thalassemia patients. Patients who were confirmed HbE/β-thalassemia were recruited and genotyping study was performed on these subjects. Ninety-eight patients were selected and divided into moderate and severe groups based on clinical parameters using Sripichai scoring system (based on hemoglobin level, spleen size, growth development, the age of first transfusion and age of disease presentation). Forty-three (44.9%) and 55 (56.1%) patients were found to have moderate and severe clinical presentation, respectively. Genotyping analysis was performed using Affymetrix 6.0 microarray platform. The SNPs were filtered using PLINK and Manhattan plot by R software. From the GWAS results, 20 most significant SNPs were selected based on disease severity when compared between moderate and severe groups. The significant SNPs found in this study were mostly related to thalassemia complications such as rs7372408, associated with KCNMB2-AS1 and SNPs associated with disease severity. These findings could be used as genetic predictors in managing patients with HbE/β-thalassemia and served as platform for future study.
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http://dx.doi.org/10.1007/s00277-020-03927-5DOI Listing
April 2020

Ancestry-informative marker (AIM) SNP panel for the Malay population.

Int J Legal Med 2020 Jan 23;134(1):123-134. Epub 2019 Nov 23.

Department of Paediatrics, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

Ancestry-informative markers (AIMs) can be used to infer the ancestry of an individual to minimize the inaccuracy of self-reported ethnicity in biomedical research. In this study, we describe three methods for selecting AIM SNPs for the Malay population (Malay AIM panel) using different approaches based on pairwise F, informativeness for assignment (I), and PCA-correlated SNPs (PCAIMs). These Malay AIM panels were extracted from genotype data stored in SNP arrays hosted by the Malaysian node of the Human Variome Project (MyHVP) and the Singapore Genome Variation Project (SGVP). In particular, genotype data from a total of 165 Malay individuals were analyzed, comprising data on 117 individual genotypes from the Affymetrix SNP-6 SNP array platform and data on 48 individual genotypes from the OMNI 2.5 Illumina SNP array platform. The HapMap phase 3 database (1397 individuals from 11 populations) was used as a reference for comparison with the Malay genotype data. The accuracy of each resulting Malay AIM panel was evaluated using a machine learning "ancestry-predictive model" constructed by using WEKA, a comprehensive machine learning platform written in Java. A total of 1250 SNPs were finally selected, which successfully identified Malay individuals from other world populations with an accuracy of 90%, but the accuracy decreased to 80% using 157 SNPs according to the pairwise F method, while a panel of 200 SNPs selected using I and PCAIMs could be used to identify Malay individuals with an accuracy of approximately 80%.
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http://dx.doi.org/10.1007/s00414-019-02184-0DOI Listing
January 2020

Quadrupole-Time-of-Flight Mass Spectrometric Identification of Hemoglobin Subunits α, β, γ and δ in Unknown Peaks of High Performance Liquid Chromatography of Hemoglobin in β-Thalassemias.

Hemoglobin 2019 May 12;43(3):182-187. Epub 2019 Jul 12.

Institute of Molecular Biosciences, Mahidol University , Salaya Campus , Nakornpathom , Thailand.

This is the first report of quadrupole time-of-flight (Q-TOF) mass spectrometric identification of the hemoglobin (Hb) subunits, α, β, δ and γ peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the cation exchange chromatography of Hb. The objectives were to identify the unknown high performance liquid chromatography (HPLC) peaks in healthy subjects and in patients with β-thalassemia (β-thal). The results demonstrate the existence of pools of free globin chains in red blood cells (RBCs). The α-, β-, δ- and γ-globin peptides were identified in the unknown HPLC peaks. The quantification and role of the free globin pool in patients with β-thal requires further investigation. Identification of all types of Hb subunits in the retention time (RT) before 1 min. suggests that altered Hbs is the nature of these fast-eluting peaks. Relevancy of thalassemias to the protein-aggregation disorders will require review of the role of free globin in the pathology of the disease.
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http://dx.doi.org/10.1080/03630269.2019.1632893DOI Listing
May 2019

Relative proteome quantification of alpha, beta, gamma and delta globin chains in early eluting peaks of Bio-Rad variant II CE-HPLC of hemoglobin from healthy and beta-thalassemia subjects in Malaysia.

Biochem Biophys Rep 2019 Jul 28;18:100635. Epub 2019 Apr 28.

Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakornpathom, 73170, Thailand.

This is the first report of QQQ-mass spectrometric identification and quantification of the Hb subunits, alpha, beta, delta and gamma globin peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the Bio-Rad cation-exchange chromatography of haemoglobin. The objectives were to assess the relationship of the quantity of the free alpha, beta, delta and gamma globin chains with the phenotypic diversity of beta-thalassaemias (β-thal). The results demonstrate that the pools of free globin chains in red blood cells were correlating with the severity of the disease in patients with different phenotypes of β-thal. The mechanism and the regulation of synthesis of free globin chains pool in a normal individual and in patients with different β-thal phenotypes could arise from several mechanisms which will require further investigation. The role of the free globin pool in patients with β-thal for development of novel therapeutic approaches based on these potential targets requires further investigation. Pertinent biomarkers improves the diagnosis of the β-thal, especially in low-income countries where they are most common and allows more effective therapeutic intervention leading to more successful therapeutic outcome.
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http://dx.doi.org/10.1016/j.bbrep.2019.100635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488526PMC
July 2019

Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies.

EBioMedicine 2017 Sep 17;23:150-159. Epub 2017 Aug 17.

Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Guangdong Key Laboratory of Biological Chip, Guangzhou, Guangdong, China.

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies.
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http://dx.doi.org/10.1016/j.ebiom.2017.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605365PMC
September 2017

Analysis of the genetic structure of the Malay population: Ancestry-informative marker SNPs in the Malay of Peninsular Malaysia.

Forensic Sci Int Genet 2017 09 14;30:152-159. Epub 2017 Jul 14.

Department of Paediatric, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150 Kelantan, Malaysia. Electronic address:

Malay, the main ethnic group in Peninsular Malaysia, is represented by various sub-ethnic groups such as Melayu Banjar, Melayu Bugis, Melayu Champa, Melayu Java, Melayu Kedah Melayu Kelantan, Melayu Minang and Melayu Patani. Using data retrieved from the MyHVP (Malaysian Human Variome Project) database, a total of 135 individuals from these sub-ethnic groups were profiled using the Affymetrix GeneChip Mapping Xba 50-K single nucleotide polymorphism (SNP) array to identify SNPs that were ancestry-informative markers (AIMs) for Malays of Peninsular Malaysia. Prior to selecting the AIMs, the genetic structure of Malays was explored with reference to 11 other populations obtained from the Pan-Asian SNP Consortium database using principal component analysis (PCA) and ADMIXTURE. Iterative pruning principal component analysis (ipPCA) was further used to identify sub-groups of Malays. Subsequently, we constructed an AIMs panel for Malays using the informativeness for assignment (I) of genetic markers, and the K-nearest neighbor classifier (KNN) was used to teach the classification models. A model of 250 SNPs ranked by I, correctly classified Malay individuals with an accuracy of up to 90%. The identified panel of SNPs could be utilized as a panel of AIMs to ascertain the specific ancestry of Malays, which may be useful in disease association studies, biomedical research or forensic investigation purposes.
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http://dx.doi.org/10.1016/j.fsigen.2017.07.005DOI Listing
September 2017

Harmonizing the interpretation of genetic variants across the world: the Malaysian experience.

BMC Res Notes 2016 Feb 26;9:125. Epub 2016 Feb 26.

Department of Pediatric, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, 16150, Kota Bharu, Kelantan, Malaysia.

Background: Databases for gene variants are very useful for sharing genetic data and to facilitate the understanding of the genetic basis of diseases. This report summarises the issues surrounding the development of the Malaysian Human Variome Project Country Node. The focus is on human germline variants. Somatic variants, mitochondrial variants and other types of genetic variation have corresponding databases which are not covered here, as they have specific issues that do not necessarily apply to germline variations.

Results: The ethical, legal, social issues, intellectual property, ownership of the data, information technology implementation, and efforts to improve the standards and systems used in data sharing are discussed.

Conclusion: An overarching framework such as provided by the Human Variome Project to co-ordinate activities is invaluable. Country Nodes, such as MyHVP, enable human gene variation associated with human diseases to be collected, stored and shared by all disciplines (clinicians, molecular biologists, pathologists, bioinformaticians) for a consistent interpretation of genetic variants locally and across the world.
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http://dx.doi.org/10.1186/s13104-015-1798-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768322PMC
February 2016

Multidrug-resistant tuberculosis and risk factors associated with its development: a retrospective study.

J Infect Dev Ctries 2015 Oct 29;9(10):1076-85. Epub 2015 Oct 29.

School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.

Introduction: Multidrug-resistant tuberculosis (MDR-TB) has emerged as a major clinical public health threat and challenges the national TB control program in Malaysia. Data that elaborates on the risk factors associated with the development of MDR-TB is highly limited in this country. This study was aimed to determine the risk factors associated with the development of MDR-TB patients in peninsular Malaysia.

Methodology: This was a case control study; the data were collected from medical records of all the registered MDR-TB patients at five referral TB hospitals in peninsular Malaysia from January 2010 to April 2014. The 105 cases were all confirmed by a positive sputum culture of Mycobacterium tuberculosis for MDR-TB and extensively drug-resistant (XDR)-TB. As a comparison, a total of 209 non-MDR-TB cases were randomly selected as controls.

Results: A total of 105 MDR-TB and 209 non MDR-TB patients were studied. The risk factors associated with MDR-TB within the multivariate analysis were previous tuberculosis treatment, HIV infection, being an immigrant, and high load of positive for acid-fast bacillus (AFB) smear.

Conclusions: The findings of this study revealed that patients who had received previous treatment for tuberculosis, were infected with HIV, were immigrants, and had a high burden of positive testing for AFB smear were more likely to have MDR-TB. An enhanced understanding of the risk factors associated with MDR-TB strains is imperative in the development of a national policy for public health interventions.
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http://dx.doi.org/10.3855/jidc.6162DOI Listing
October 2015

Prevalence of Helicobacter pylori cagA, babA2, and dupA genotypes and correlation with clinical outcome in Malaysian patients with dyspepsia.

Turk J Med Sci 2015 ;45(4):940-6

Background/aim: The severity of disease outcome in dyspepsia has been attributed to Helicobacter pylori virulence genes. The aim of this study was to determine the distribution of H. pylori virulence genes (cagA, babA2, and dupA) and to determine whether or not there arises a significant correlation with clinical dyspepsia outcomes.

Materials And Methods: H. pylori genotypes cagA, babA2, and dupA were identified by polymerase chain reactions from gastric biopsy samples in 105 H. pylori-positive patients.

Results: The positive rates for cagA, babA2, and dupA genes in H. pylori dyspeptic patients were 69.5%, 41.0%, and 22.9%, respectivel cagA was more prevalent in Indians (39.7%), babA2 was more prevalent in Malays (39.5%), and dupA detection occurred more frequently in both Indians and Malays and at the same rate (37.5%). The Chinese inhabitants had the lowest prevalence of the three genes. Nonulcer disease patients had a significantly higher distribution of cagA (76.7%), babA2 (74.4%), and dupA (75.0%). There was no apparent association between these virulence genes and the clinical outcomes.

Conclusion: The lower prevalence of these genes and variations among different ethnicities implies that the strains are geographically and ethnically dependent. None of the virulence genes were knowingly beneficial in predicting the clinical outcome of H. pylori infection in our subjects.
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http://dx.doi.org/10.3906/sag-1409-77DOI Listing
October 2015

Dissecting the genetic structure and admixture of four geographical Malay populations.

Sci Rep 2015 Sep 23;5:14375. Epub 2015 Sep 23.

Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

The Malay people are an important ethnic composition in Southeast Asia, but their genetic make-up and population structure remain poorly studied. Here we conducted a genome-wide study of four geographical Malay populations: Peninsular Malaysian Malay (PMM), Singaporean Malay (SGM), Indonesian Malay (IDM) and Sri Lankan Malay (SLM). All the four Malay populations showed substantial admixture with multiple ancestries. We identified four major ancestral components in Malay populations: Austronesian (17%-62%), Proto-Malay (15%-31%), East Asian (4%-16%) and South Asian (3%-34%). Approximately 34% of the genetic makeup of SLM is of South Asian ancestry, resulting in its distinct genetic pattern compared with the other three Malay populations. Besides, substantial differentiation was observed between the Malay populations from the north and the south, and between those from the west and the east. In summary, this study revealed that the genetic identity of the Malays comprises a mixed entity of multiple ancestries represented by Austronesian, Proto-Malay, East Asian and South Asian, with most of the admixture events estimated to have occurred 175 to 1,500 years ago, which in turn suggests that geographical isolation and independent admixture have significantly shaped the genetic architectures and the diversity of the Malay populations.
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http://dx.doi.org/10.1038/srep14375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585825PMC
September 2015

Fine-scale population structure of Malays in Peninsular Malaysia and Singapore and implications for association studies.

Hum Genomics 2015 Jul 22;9:16. Epub 2015 Jul 22.

Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Fine scale population structure of Malays - the major population in Malaysia, has not been well studied. This may have important implications for both evolutionary and medical studies. Here, we investigated the population sub-structure of Malay involving 431 samples collected from all states from peninsular Malaysia and Singapore. We identified two major clusters of individuals corresponding to the north and south peninsular Malaysia. On an even finer scale, the genetic coordinates of the geographical Malay populations are in correlation with the latitudes (R(2) = 0.3925; P = 0.029). This finding is further supported by the pairwise FST of Malay sub-populations, of which the north and south regions showed the highest differentiation (FST [North-south] = 0.0011). The collective findings therefore suggest that population sub-structure of Malays are more heterogenous than previously expected even within a small geographical region, possibly due to factors like different genetic origins, geographical isolation, could result in spurious association as demonstrated in our analysis. We suggest that cautions should be taken during the stage of study design or interpreting the association signals in disease mapping studies which are expected to be conducted in Malay population in the near future.
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http://dx.doi.org/10.1186/s40246-015-0039-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509480PMC
July 2015

Analysis of Hereditary Nonpolyposis Colorectal Cancer in Malay Cohorts using Immunohistochemical Screening.

Asian Pac J Cancer Prev 2015 ;16(9):3767-71

Department of Paediatric, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kelantan, Malaysia E-mail :

Background: Lynch syndrome (LS) is an inherited predisposition to colorectal, endometrial (uterine) and other cancers. Although most cancers are not inherited, about 5 percent (%) of people who have colorectal or endometrial cancer have the Lynch syndrome. It involves the alteration of mismatch repair (MMR) genes; MLH1, MSH2, MSH6 or PMS2. In this study, we analyzed the expression of MMR proteins in colorectal cancer in a Malay cohort by immunohistochemistry.

Materials And Methods: A total of 17 patients were selected fulfilling one of the Bethesda criteria: colorectal cancer diagnosed in a patient aged less than 50 years old, having synchronous and metachronous colorectal cancer or with a strong family history. Immunohistochemical staining was performed on paraffin embedded tumour tissue samples using four antibodies: MLH1, MSH2, MSH6 and PMS2.

Results: Twelve out of 17 patients (70.6%) were noted to have a family history. A total of 41% (n=7) of the patients had abnormal immunohistochemical staining with one or more of the four antibodies. Loss of expression were noted in 13 tumour tissues with a negative staining score <4. Of 13 tumour tissues, four showed loss expression of MLH1. For PMS2, loss of expression were noted in five cases. Both MSH2 and MSH6 showed loss of expression in two tumour tissues respectively.

Conclusions: Revised Bethesda criteria and immunohistochemical analysis constituted a convenient approach and is recommended to be a first-line screening for Lynch syndrome in Malay cohorts.
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http://dx.doi.org/10.7314/apjcp.2015.16.9.3767DOI Listing
February 2016

The first Malay database toward the ethnic-specific target molecular variation.

BMC Res Notes 2015 Apr 30;8:176. Epub 2015 Apr 30.

Department of Pediatric, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia.

Background: The Malaysian Node of the Human Variome Project (MyHVP) is one of the eighteen official Human Variome Project (HVP) country-specific nodes. Since its inception in 9(th) October 2010, MyHVP has attracted the significant number of Malaysian clinicians and researchers to participate and contribute their data to this project. MyHVP also act as the center of coordination for genotypic and phenotypic variation studies of the Malaysian population. A specialized database was developed to store and manage the data based on genetic variations which also associated with health and disease of Malaysian ethnic groups. This ethnic-specific database is called the Malaysian Node of the Human Variome Project database (MyHVPDb).

Findings: Currently, MyHVPDb provides only information about the genetic variations and mutations found in the Malays. In the near future, it will expand for the other Malaysian ethnics as well. The data sets are specified based on diseases or genetic mutation types which have three main subcategories: Single Nucleotide Polymorphism (SNP), Copy Number Variation (CNV) followed by the mutations which code for the common diseases among Malaysians. MyHVPDb has been open to the local researchers, academicians and students through the registration at the portal of MyHVP ( http://hvpmalaysia.kk.usm.my/mhgvc/index.php?id=register ).

Conclusions: This database would be useful for clinicians and researchers who are interested in doing a study on genomics population and genetic diseases in order to obtain up-to-date and accurate information regarding the population-specific variations and also useful for those in countries with similar ethnic background.
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http://dx.doi.org/10.1186/s13104-015-1123-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440489PMC
April 2015

A genome wide pattern of population structure and admixture in peninsular Malaysia Malays.

Hugo J 2014 Dec 30;8(1). Epub 2014 Oct 30.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kelantan, Malaysia.

Background: The Malays consist of various sub-ethnic groups which are believed to have different ancestral origins based on their migrations centuries ago. The sub-ethnic groups can be divided based on the region they inhabit; the northern (Melayu Kedah and Melayu Kelantan), western (Melayu Minang) and southern parts (Melayu Bugis and Melayu Jawa) of Peninsular Malaysia. We analyzed 54,794 autosomal single nucleotide polymorphisms (SNPs) which were shared by 472 unrelated individuals from 17 populations to determine the genetic structure and distributions of the ancestral genetic components in five Malay sub-ethnic groups namely Melayu Bugis, Melayu Jawa, Melayu Minang, Melayu Kedah, and Melayu Kelantan. We also have included in the analysis 12 other study populations from Thailand, Indonesia, China, India, Africa and Orang Asli sub-groups in Malay Peninsula, obtained from the Pan Asian SNP Initiative (PASNPI) Consortium and International HapMap project database.

Results: We found evidence of genetic influx from Indians to Malays, more in Melayu Kedah and Melayu Kelantan which are genetically different from the other Malay sub-ethnic groups, but similar to Thai Pattani. More than 98% of these northern Malays haplotypes could be found in either Indians or Chinese populations, indicating a highly admixture pattern among populations. Nevertheless, the ancestry lines of Malays, Indonesians and Thais were traced back to have shared a common ancestor with the Proto-Malays and Chinese.

Conclusions: These results support genetic admixtures in the Peninsular Malaysia Malay populations and provided valuable information on the enigmatic demographical history as well as shed some insights into the origins of the Malays in the Malay Peninsula.
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http://dx.doi.org/10.1186/s11568-014-0005-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735395PMC
December 2014

A whole genome analyses of genetic variants in two Kelantan Malay individuals.

Hugo J 2014 Dec 21;8(1). Epub 2014 Oct 21.

Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: The sequencing of two members of the Royal Kelantan Malay family genomes will provide insights on the Kelantan Malay whole genome sequences. The two Kelantan Malay genomes were analyzed for the SNP markers associated with thalassemia and Helicobacter pylori infection. Helicobacter pylori infection was reported to be low prevalence in the north-east as compared to the west coast of the Peninsular Malaysia and beta-thalassemia was known to be one of the most common inherited and genetic disorder in Malaysia.

Result: By combining SNP information from literatures, GWAS study and NCBI ClinVar, 18 unique SNPs were selected for further analysis. From these 18 SNPs, 10 SNPs came from previous study of Helicobacter pylori infection among Malay patients, 6 SNPs were from NCBI ClinVar and 2 SNPs from GWAS studies. The analysis reveals that both Royal Kelantan Malay genomes shared all the 10 SNPs identified by Maran (Single Nucleotide Polymorphims (SNPs) genotypic profiling of Malay patients with and without Helicobacter pylori infection in Kelantan, 2011) and one SNP from GWAS study. In addition, the analysis also reveals that both Royal Kelantan Malay genomes shared 3 SNP markers; HBG1 (rs1061234), HBB (rs1609812) and BCL11A (rs766432) where all three markers were associated with beta-thalassemia.

Conclusions: Our findings suggest that the Royal Kelantan Malays carry the SNPs which are associated with protection to Helicobacter pylori infection. In addition they also carry SNPs which are associated with beta-thalassemia. These findings are in line with the findings by other researchers who conducted studies on thalassemia and Helicobacter pylori infection in the non-royal Malay population.
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http://dx.doi.org/10.1186/s11568-014-0004-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685156PMC
December 2014

Multiplex amplification refractory mutation system (MARMS) for the detection of β-globin gene mutations among the transfusion-dependent β-thalassemia Malay patients in Kelantan, Northeast of Peninsular Malaysia.

Am J Blood Res 2014 5;4(1):33-40. Epub 2014 Sep 5.

Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia Malaysia.

The aim of this study was to adapt MARMS with some modifications to detect beta mutation in our cohort of thalassemia patients. We focused only on transfusion-dependent thalassemia Malay patients, the predominant ethnic group (95%) in the Kelantanese population. Eight mutations were identified in 46 out of 48 (95.83%) beta thalassemia alleles. Most of the patients (54.2%) were compound heterozygous with co-inheritance Cd 26 (G>A). The frequencies of spectrum beta chain mutation among these patients are presented in Table 2. Among the transfusion dependent beta thalassemia Malay patients studied, 26 patients were found to be compound heterozygous and the main alleles were Cd 26 (G>A). Compound heterozygous mutation of Cd 26 (G>A) and IVS 1-5 (G>C) were 12 (46.2%), Cd 26 (G>A) and Cd 41/42 (TTCT) were 9 (34.6%), Cd 26 (G>A) and IVS 1-1 (G>C) were 2 (7.7%) respectively. Meanwhile the minority were made of a single compound heterozygous of Cd 26 (G>A) and Cd 71/72, Cd 26 (>A) and Cd 17 (A>T), Cd 26 (G>A) and -28 (G>A) respectively. Twenty out of forty six patients were shown to have homozygous of IVS 1-5 (G>C) were 2 (10.0%), Cd 26 (G>A) were 15 (75.0%), Cd 19 (A>G) were 1 (5.0%), and IVS 1-1 (G>T) were 2 (10.0%). The beta chain mutations among the Kelantanese Malays followed closely the distribution of beta chain mutations among the Thais and the Malays of the Southern Thailand. The G-C transition at position 5 of the IVS 1-5 mutation was predominant among the Malay patients. In conclusion, this method has successfully identified the mutation spectrum in our cohort of transfusion-dependent beta thalassemia patients, and this method is equally effective in screening for mutation among thalassemia patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165115PMC
September 2014

Evaluation of the Atlas Helicobacter pylori stool antigen test for diagnosis of infection in adult patients.

Asian Pac J Cancer Prev 2014 ;15(13):5245-7

Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia E-mail :

Background: Helicobacter pylori (H. pylori) is one of the most important causes of dyspepsia and gastric cancer and diagnosis can be made by invasive or non-invasive methods. The Atlas Helicobacter pylori antigen test is a new rapid non-invasive method which is simple to conduct. The aim of this study was to determine its sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy.

Materials And Methods: This prospective study was conducted between July 2012 and December 2013. Stool samples of 59 dyspeptic patients who underwent upper endoscopy were evaluated for H. pylori stool antigen.

Results: From the 59 patients who participated in this study, there were 36 (61%) males and 23 (39%) females. H. pylori was diagnosed in 24 (40.7%) gastric biopsies, 22 (91.7 %) of these being positive for the Atlas H. pylori antigen test. The sensitivity, specificity, PPV, NPV and accuracy were 91.7%, 100%, 100%, 94.6% and 96.6% respectively.

Conclusions: The Atlas H. pylori antigen test is a new non-invasive method which is simple to perform and avails reliable results in a few minutes. Thus it can be the best option for the diagnosis of H. pylori infection due to its high sensitivity and specificity.
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http://dx.doi.org/10.7314/apjcp.2014.15.13.5245DOI Listing
April 2015

The population genomic landscape of human genetic structure, admixture history and local adaptation in Peninsular Malaysia.

Hum Genet 2014 Sep 11;133(9):1169-85. Epub 2014 Jun 11.

Max Planck Independent Research Group on Population Genomics, Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Peninsular Malaysia is a strategic region which might have played an important role in the initial peopling and subsequent human migrations in Asia. However, the genetic diversity and history of human populations--especially indigenous populations--inhabiting this area remain poorly understood. Here, we conducted a genome-wide study using over 900,000 single nucleotide polymorphisms (SNPs) in four major Malaysian ethnic groups (MEGs; Malay, Proto-Malay, Senoi and Negrito), and made comparisons of 17 world-wide populations. Our data revealed that Peninsular Malaysia has greater genetic diversity corresponding to its role as a contact zone of both early and recent human migrations in Asia. However, each single Orang Asli (indigenous) group was less diverse with a smaller effective population size (N(e)) than a European or an East Asian population, indicating a substantial isolation of some duration for these groups. All four MEGs were genetically more similar to Asian populations than to other continental groups, and the divergence time between MEGs and East Asian populations (12,000--6,000 years ago) was also much shorter than that between East Asians and Europeans. Thus, Malaysian Orang Asli groups, despite their significantly different features, may share a common origin with the other Asian groups. Nevertheless, we identified traces of recent gene flow from non-Asians to MEGs. Finally, natural selection signatures were detected in a batch of genes associated with immune response, human height, skin pigmentation, hair and facial morphology and blood pressure in MEGs. Notable examples include SYN3 which is associated with human height in all Orang Asli groups, a height-related gene (PNPT1) and two blood pressure-related genes (CDH13 and PAX5) in Negritos. We conclude that a long isolation period, subsequent gene flow and local adaptations have jointly shaped the genetic architectures of MEGs, and this study provides insight into the peopling and human migration history in Southeast Asia.
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http://dx.doi.org/10.1007/s00439-014-1459-8DOI Listing
September 2014

Novel complex re-arrangement of ARG1 commonly shared by unrelated patients with hyperargininemia.

Gene 2014 Jan 5;533(1):240-5. Epub 2013 Oct 5.

Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: Hyperargininemia is a very rare progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. Until now, some mutations were reported worldwide and none of them were of Southeast Asian origins. Furthermore, most reported mutations were point mutations and a few others deletions or insertions.

Objective: This study aims at identifying the disease-causing mutation in the ARG1 gene of Malaysian patients with hyperargininemia.

Methodology: We employed a series of PCR amplifications and direct sequencing in order to identify the mutation. We subsequently used quantitative real-time PCR to determine the copy number of the exons flanking the mutation. We blasted our sequencing data with that of the reference sequence in the NCBI in order to obtain positional insights of the mutation.

Results: We found a novel complex re-arrangement involving insertion, inversion and gross deletion of ARG1 (designated g.insIVS1+1899GTTTTATCAT;g.invIVS1+1933_+1953;g.delIVS1+1954_IVS2+914;c.del116_188;p.Pro20SerfsX4) commonly shared by 5 patients with hyperargininemia, each originating from different family. None of the affected families share known relationship with each other, although four of the five patients were known to have first-cousin consanguineous parents.

Conclusion: This is the first report of complex re-arrangement in the ARG1. Further analyses showing that the patients have shared the same geographic origin within the northeastern part of Malaysia prompted us to suggest a simple molecular screening of hyperargininemia within related ethnicities using a long-range PCR.
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http://dx.doi.org/10.1016/j.gene.2013.09.081DOI Listing
January 2014

Gastric precancerous lesions are associated with gene variants in Helicobacter pylori-susceptible ethnic Malays.

World J Gastroenterol 2013 Jun;19(23):3615-22

School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Malaysia.

Aim: To identify genes associated with gastric precancerous lesions in Helicobacter pylori (H. pylori)-susceptible ethnic Malays.

Methods: Twenty-three Malay subjects with H. pylori infection and gastric precancerous lesions identified during endoscopy were included as "cases". Thirty-seven Malay subjects who were H. pylori negative and had no precancerous lesions were included as "controls". Venous blood was collected for genotyping with Affymetrix 50K Xba1 kit. Genotypes with call rates < 90% for autosomal single nucleotide polymorphisms (SNPs) were excluded. For each precancerous lesion, associated SNPs were identified from Manhattan plots, and only SNPs with a χ² P value < 0.05 and Hardy Weinberg Equilibrium P value > 0.5 was considered as significant markers.

Results: Of the 23 H. pylori-positive subjects recruited, one sample was excluded from further analysis due to a low genotyping call rate. Of the 22 H. pylori-positive samples, atrophic gastritis only was present in 50.0%, complete intestinal metaplasia was present in 18.25%, both incomplete intestinal metaplasia and dysplasia was present in 22.7%, and dysplasia only was present in 9.1%. SNPs rs9315542 (UFM1 gene), rs6878265 (THBS4 gene), rs1042194 (CYP2C19 gene) and rs10505799 (MGST1 gene) were significantly associated with atrophic gastritis, complete intestinal metaplasia, incomplete metaplasia with foci of dysplasia and dysplasia, respectively. Allele frequencies in "cases" vs "controls" for rs9315542, rs6878265, rs1042194 and rs10505799 were 0.4 vs 0.06, 0.6 vs 0.01, 0.6 vs 0.01 and 0.5 vs 0.02, respectively.

Conclusion: Genetic variants possibly related to gastric precancerous lesions in ethnic Malays susceptible to H. pylori infection were identified for testing in subsequent trials.
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http://dx.doi.org/10.3748/wjg.v19.i23.3615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691040PMC
June 2013

Molecular description of familial defective APOB-100 in Malaysia.

Biochem Genet 2013 Oct 18;51(9-10):811-23. Epub 2013 Jun 18.

Medical Cluster, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia,

Familial ligand-defective apolipoprotein B-100 is characterized by elevated plasma low-density lipoprotein levels and premature heart disease. This study aims to determine apolipoprotein B gene mutations among Malaysians with clinical diagnoses of familial hypercholesterolemia and to compare the phenotype of patients with apolipoprotein B gene mutations to those with a low-density lipoprotein receptor gene mutation. A group of 164 patients with a clinical diagnosis of familial hypercholesterolemia was analyzed. Amplicons in exon 26 and exon 29 of the apolipoprotein B gene were screened for genetic variants using denaturing gradient high-performance liquid chromatography; 10 variants were identified. Five novel mutations were detected (p.Gln2485Arg, p.Thr3526Ala, p.Glu3666Lys, p.Tyr4343CysfsX221, and p.Arg4297His). Those with familial defective apolipoprotein had a less severe phenotype than those with familial hypercholesterolemia. An apolipoprotein gene defect is present among Malaysian familial hypercholesterolemics. Those with both mutations show a more severe phenotype than those with one gene defect.
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http://dx.doi.org/10.1007/s10528-013-9609-6DOI Listing
October 2013

Mutation spectrum of dystrophin gene in malaysian patients with Duchenne/Becker muscular dystrophy.

J Neurogenet 2013 Jun 26;27(1-2):11-5. Epub 2013 Feb 26.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, Kelantan, Malaysia.

We undertook the clinical feature examination and dystrophin analysis using multiplex ligation-dependent probe amplification (MLPA) and direct DNA sequencing of selected exons in a cohort of 35 Malaysian Duchenne/Becker muscular dystrophy (DMD/BMD) patients. We found 27 patients with deletions of one or more exons, 2 patients with one exon duplication, 2 patients with nucleotide deletion, and 4 patients with nonsense mutations (including 1 patient with two nonsense mutations in the same exon). Although most cases showed compliance to the reading frame rule, we found two unrelated DMD patients with an in-frame deletion of the gene. Two novel mutations have been detected in the Dystrophin gene and our results were compatible with other studies where the majority of the mutations (62.8%) are located in the distal hotspot. However, the frequency of the mutations in our patient varied as compared with those found in other populations.
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http://dx.doi.org/10.3109/01677063.2012.762580DOI Listing
June 2013

Towards understanding the low prevalence of Helicobacter pylori in Malays: genetic variants among Helicobacter pylori-negative ethnic Malays in the north-eastern region of Peninsular Malaysia and Han Chinese and South Indians.

J Dig Dis 2013 Apr;14(4):196-202

Human Genome Center, Universiti Sains Malaysia, Kota Bahru, Malaysia.

Objectives: To identify gene polymorphisms that differ between Malays, Han Chinese and South Indians, and to identify candidate genes for the investigation of their role in protecting Malays from Helicobacter pylori (H. pylori) infection.

Methods: Malay participants born and residing in Kelantan with a documented absence of H. pylori infection were studied. Venous blood was used for genotyping using the Affymetrix 50K Xba I kit. CEL files from 141 Han Chinese and 76 South Indians were analyzed to compare their allele frequency with that of the Malays using fixation index (FST ) calculation. The single nucleotide polymorphisms (SNPs) with the highest allele frequency (outliers) were then examined for their functional characteristics using F-SNP software and the Entrez Gene database.

Results: In all, 37 Malays were enrolled in the study; of whom 7 were excluded for low genotyping call rates. The average FST estimated from the genome-wide data were 0.038 (Malays in Kelantan vs the South Indians), 0.015 (Malays in Kelantan vs Han Chinese) and 0.066 (Han Chinese vs South Indians), respectively. The outlier gene variants present in Malays with functional characteristics were C7orf10 (FST  0.29988), TSTD2 (FST  0.43278), SMG7 (FST  0.29877) and XPA (FST  0.43393 and 0.43644).

Conclusion: Genetic variants possibly related to protection against H. pylori infection in ethnic Malays from the north-eastern region of Peninsular Malaysia were identified for testing in subsequent trials among infected and uninfected Malays.
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http://dx.doi.org/10.1111/1751-2980.12023DOI Listing
April 2013

Deleted in Colorectal Cancer (DCC) gene polymorphism is associated with H. pylori infection among susceptible Malays from the north-eastern region of Peninsular Malaysia.

Hepatogastroenterology 2013 Jan-Feb;60(121):124-8

Human Genome Center, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Background/aims: Using genome-wide case-control association approach, the current study aimed to determine whether genetic polymorphism(s) is/are associated with H. pylori infection among ethnic Malays from the north-eastern region of Peninsular Malaysia, a region with an exceptionally low prevalence for H. pylori infection and gastric cancer.

Methodology: Twenty-three Malay subjects positive for H. pylori confirmed with urease test and histology were enrolled as "cases" and 37 subjects negative for H. pylori were "controls". Both groups were matched for age and environmental risks. Extracted DNA samples (QIAGEN, Germany) from the venous blood of study subjects were genotyped using the Human Mapping 50k xbal array (Affymetrix, USA). High throughput downstream analyses were then used to determine the significant SNP(s) associated with H. pylori infection.

Results: Out of 20,361 SNPs filtered using the genotype association test, the top 1% (203) significant SNPs were selected for functional enrichment analysis. Of the 15 "enriched" SNPs, the rs10502974 which was located within the intronic region of Deleted in Colorectal Cancer (DCC) gene was the SNP most significantly associated with H. pylori infection (p=0.00549).

Conclusions: Ethnic Malays is genetically susceptible to H. pylori infection and is possibly mediated through a genetic variation in the DCC gene.
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http://dx.doi.org/10.5754/hge12471DOI Listing
July 2013

Human Variome Project country nodes: documenting genetic information within a country.

Hum Mutat 2012 Nov 18;33(11):1513-9. Epub 2012 Jul 18.

Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.

The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.
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http://dx.doi.org/10.1002/humu.22147DOI Listing
November 2012

Mutation screening of IRF6 among families with non-syndromic oral clefts and identification of two novel variants: review of the literature.

Eur J Med Genet 2012 Jun 3;55(6-7):389-93. Epub 2012 Mar 3.

Human Genome Center, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Non-syndromic oral clefts share the main clinical features of Van der Woude Syndrome (VWS), with the exception of the lower lip pit. Thus, about 15% of VWS cases are indistinguishable from cases with non-syndromic oral clefts. IRF6 mutations are the major cause of VWS; however, variants in this gene show strong association with non-syndromic oral clefts, with a higher increased risk among cases with cleft lip only (CLO). A total of 39 individuals, including 16 patients with CLO and 23 patients with a family history of cleft, were examined for IRF6 mutations in the present study. Seven variants, including five known (c.-75-4 A>; G, c.-73T>; C, c.459G>; T 5, c.820G>; A, and c.1060 + 37C>; T) and two novel (c.-75-23G>; C and c.1380G>; T), were found. Both novel variants were inherited from non-affected parents and we did not find also in the 120 control chromosomes. In silico analysis revealed that both c.1380G>; T and c.-75-23G>; C variants may disrupts a putative exonic splicing enhancer and intronic splicing binding site for SC35, respectively. Taken together, the presence of deleterious IRF6 variants in patients with non-syndromic oral clefts could be most likely an evidence for VWS. While, IRF6 variants could, at best, contribute to clefting as part of a complex inheritance pattern, with both additional genes and environmental factors having a role.
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http://dx.doi.org/10.1016/j.ejmg.2012.02.006DOI Listing
June 2012

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population.

J Hum Genet 2011 Nov 25;56(11):755-8. Epub 2011 Aug 25.

Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Oral clefts are clinically and genetically heterogeneous disorders that are influenced by both genetic and environmental factors. The present family-based association study investigated the role of the MSX1 and TGFB3 genes in the etiology of non-syndromic oral cleft in a Malay population. No transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, whereas TGFB3-CA exhibited a trend to excess maternal transmission. In sequencing the MSX1 coding regions in 124 patients with oral cleft, five variants were found, including three known variants (A34G, G110G and P147Q) and two novel variants (M37L and G267A). The P147Q and M37L variants were not observed in 200 control chromosomes, whereas G267A was found in one control sample, indicating a very rare polymorphic variant. Furthermore, the G110G variant displayed a significant association between patients with non-syndromic cleft lip, with or without cleft palate, and normal controls (P=0.001, odds ratio=2.241, 95% confidence interval, 1.357-3.700). Therefore, these genetic variants may contribute, along with other genetic and environmental factors, to this condition.
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http://dx.doi.org/10.1038/jhg.2011.95DOI Listing
November 2011

Contribution of variants in and near the IRF6 gene to the risk of nonsyndromic cleft lip with or without cleft palate in a Malay population.

Am J Med Genet A 2011 Sep 10;155A(9):2302-7. Epub 2011 Aug 10.

Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Several studies have shown evidence for the contribution of interferon regulatory factor 6 (IRF6) variants to the risk of nonsyndromic oral clefts in Asians; however, this has not included the Malay population. The current study attempts to address this research gap using allele and haplotype transmission disequilibrium analyses. The results showed a strong transmission distortion for multiple haplotypes to patients with nonsyndromic cleft lip with or without cleft palate. Haplotypes carrying the 243 bp allele of D1S2136 and common alleles at the rs861019 and rs2235371 were over-transmitted to patients. By contrast, haplotypes consisting of the 251 bp allele of D1S2136 and the rare allele at rs2235371 were more under-transmitted. Furthermore, several variants and haplotypes showed excess maternal transmission, but none of them attained statistical significance in maternal relative risk analyses. In contrast, a significant child genotype effect was observed for several haplotypes, indicating fetal genotype could be the major genetic contribution rather than maternal genotype. The present study therefore further supports a role for IRF6 variants in clefting in this Southeast Asian population. Overall, Asian genetic backgrounds are most likely more susceptible to the haploinsufficiency of IRF6 variants. These variants may contribute to the condition either themselves, or they may be in linkage disequilibrium with other casual variants.
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http://dx.doi.org/10.1002/ajmg.a.34169DOI Listing
September 2011