MyMedR

Editorial: Insights in thalassemia: from genomics to clinical practice

Silao CLT, Latiff ZA, Kountouris P, Zilfalil BA

Front Pediatr, 2023;11:1222946.

PMID: 37520048 DOI: 10.3389/fped.2023.1222946

Fulltext Contribution of 6p24 to non-syndromic cleft lip and palate in a Malay population: association of variants in OFC1

Salahshourifar I, Halim AS, Sulaiman WA, Zilfalil BA

J Dent Res, 2011 Mar;90(3):387-91.

PMID: 21297019 DOI: 10.1177/0022034510391798

Non-syndromic cleft lip, with or without cleft palate, is a heterogeneous, complex disease with a high incidence in the Asian population. Several association studies have been done on cleft candidate genes, but no reports have been published thus far on the Orofacial Cleft 1 (OFC1) genomic region in an Asian population. This study investigated the association between the OFC1 genomic region and non-syndromic cleft lip with or without cleft palate in 90 Malay father-mother-offspring trios. Results showed a preferential over-transmission of a 101-bp allele of marker D6S470 in the allele- and haplotype-based transmission disequilibrium test (TDT), as well as an excess of maternal transmission. However, no significant p-value was found for a maternal genotype effect in a log-linear model, although single and double doses of the 101-bp allele showed a slightly increased cleft risk (RR = 1.37, 95% CI, 0.527-3.4, p-value = 0.516). Carrying two copies of the 101-bp allele was significantly associated with an increased cleft risk (RR = 2.53, 95% CI, 1.06-6.12, p-value = 0.035). In conclusion, we report evidence of the contribution of the OFC1 genomic region to the etiology of clefts in a Malay population.

De novo interstitial deletion of 1q32.2-q32.3 including the entire IRF6 gene in a patient with oral cleft and other dysmorphic features

Salahshourifar I, Halim AS, Sulaiman WA, Ariffin R, Naili Muhamad Nor N, Zilfalil BA

Cytogenet Genome Res, 2011;134(2):83-7.

PMID: 21447942 DOI: 10.1159/000325541

Microdeletion of the Van der Woude syndrome (VWS) critical region is a relatively rare event, and only a few cases have been reported in the medical literature. The extent of the deletion and the genotype-phenotype correlation are 2 crucial issues.

A new method for FMR1 gene methylation screening by multiplex methylation-specific real-time polymerase chain reaction

Elias MH, Ankathil R, Salmi AR, Sudhikaran W, Limprasert P, Zilfalil BA

Genet Test Mol Biomarkers, 2011 Jun;15(6):387-93.

PMID: 21329465 DOI: 10.1089/gtmb.2010.0191

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation in men. It is caused by abnormalities in the FMR1 gene that are associated with CGG repeat expansion and the hypermethylation status of its promoter. Methylated alleles lead to transcriptional inhibition and consequent loss of Fragile X Mental Retardation Protein. Chemical modification of cytosine to uracil by bisulfite treatment has proved to be an attractive method for DNA methylation studies that precludes labor-intensive Southern blot analysis, which is the gold standard test for FXS. In this report, bisulfite-treated DNA samples were amplified using real-time multiplex methylation-specific polymerase chain reaction followed by melting curve analysis. Our results show that all control samples with known CGG repeat numbers and methylation statuses were correctly diagnosed. The samples from 43 male patients were also successfully diagnosed, which were in complete agreement with the results of Southern blotting. By such means, 39 patients were found to have an unmethylated allele; 3, a fully mutated allele; and 1, both methylated and unmethylated alleles, thus implying a diagnosis of mosaicism. In conclusion, we find our method to be convenient for screening a large number of male patients with FXS, because it is rapid and easy to perform, especially when there is a low quantity of DNA that must be sensitively and accurately assayed.

Lipid profile parameters in Malaysian dyslipidemic patients

Al-Khateeb A, Mohamed MS, Imran K, Ibrahim S, Zilfalil BA, Yusof Z

Kobe J Med Sci, 2011;57(2):E38-48.

PMID: 22926072

The importance of serum lipids as cardiovascular risk factors is well recognized. However, most published studies have focused on western countries. The present study aimed to describe and analyze the lipid profile parameters in Malaysian dyslipidemic patients, and to identify concomitant clinical problems and risk factors associated with cardiovascular disease (CVD) among such patients.

De novo ring chromosome 6 in a child with multiple congenital anomalies

Ahzad HA, Ramli SF, Loong TM, Salahshourifar I, Zilfalil BA, Yusoff NM

Kobe J Med Sci, 2010;56(2):E79-84.

PMID: 21063149

Ring chromosome 6, especially if it is de novo, is a rare occurrence. The phenotype of patients with ring chromosome 6 can be highly variable ranging from almost normal to severe malformations and mental retardation. The size and structure of the ring chromosome as well as the level of mosaicism are important factors in determining the clinical phenotype. Here we report an eight month-old child, a product of a non consanguineous marriage, who presented with developmental retardation, hypertelorism, microcephaly, flat occiput, broad nasal bridge, large ears, micrognathia, wide spaced nipples, protruding umbilicus, short stubby fingers, clinodactyly, single palmar crease, short neck with no obvious webbing, and congenital heart defect. Conventional karyotyping and Whole Chromosome Paint of the peripheral leukocytes showed 46,XY,r(6)(p25q27) karyotype with plausible breakpoints at p25 and q27 end. Conventional karyotyping of both parents showed normal karyotype. To the best of our knowledge, this is the first report of a Malay individual with ring chromosome 6, and this report adds to the collective knowledge of this rare chromosome abnormality.

RB pocket domain B mutation frequency in Malaysia

Ishak SR, Hanafi H, Alagaratnam JV, Zilfalil BA, Tajudin LS

Ophthalmic Genet., 2010 Sep;31(3):159-61.

PMID: 20565234 DOI: 10.3109/13816810.2010.492816

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.

Deletion analyses of SMN1 and NAIP genes in Malaysian spinal muscular atrophy patients

Watihayati MS, Zabidi-Hussin AM, Tang TH, Matsuo M, Nishio H, Zilfalil BA

Pediatr Int, 2007 Feb;49(1):11-4.

PMID: 17250498

The survival motor neuron 1 (SMN1) gene has been recognized to be responsible for spinal muscular atrophy (SMA) because it is homozygously deleted in more than 90% of SMA patients, irrespective of their clinical severity, whereas the neuronal apoptosis inhibitory protein (NAIP) gene is now considered to be a modifying factor of the severity of SMA. In Malaysia, it remains to be elucidated whether deletion of the SMN1 gene is also a main cause of SMA or whether deletion of the NAIP gene is found in the SMA patients.

An improved rapid genotyping method for the study of beta-2 adrenergic receptor gene polymorphisms using single tube allele specific multiplex PCR

Zilfalil BA, Hoh BP, Nizam MZ, Liza-Sharmini AT, Teh LK, Ismail R

J Clin Pharm Ther, 2006 Dec;31(6):637-40.

PMID: 17176369

Seventeen single nucleotide polymorphisms (SNPs) have been identified so far, within the beta-2 receptor (beta(2) AR) gene. The presence of so many SNPs within the beta(2) AR gene causes a problem, for those studying beta(2) AR pharmacogenetics, in relation to which SNPs to choose. Most of the work has focused on the three common SNPs within the coding block (alleles 16, 27 and 164) and the techniques developed have been for these three functionally important alleles.

Fulltext Phenotype-genotype analyses of clinically diagnosed Malaysian familial hypercholestrolemic patients

Al-Khateeb A, Al-Talib H, Mohamed MS, Yusof Z, Zilfalil BA

Adv Clin Exp Med, 2013 Jan-Feb;22(1):57-67.

PMID: 23468263

BACKGROUND: Familial hypercholesterolemia and familial defective apo lipoprotein B are genetic disorders caused by defects in the low-density lipoprotein receptor gene and apo lipoprotein B 100 genes, respectively. The clinical phenotype of both diseases is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature coronary heart disease.
OBJECTIVES: The aim of this study is to perform an association study between different gene sequence variants in low-density lipoprotein and apo lipoprotein B 100 genes to the clinical finding and lipid profile parameters of the study subjects.
MATERIAL AND METHODS: A group of 164 familial hypercholesterolemic patients were recruited. The promoter region, exon 2-15 of the low density lipoprotein gene and parts of exon 26 and 29 of apo lipoprotein B 100 gene were screened by Denaturating Gradient High Performance Liquid Chromatography.
RESULTS: For the apo lipoprotein B 100 gene, those with apo lipoprotein B 100 gene mutation have a significantly higher frequency of cardiovascular disease (P = 0.045), higher low density lipoprotein cholesterol and total cholesterol: high density lipoprotein cholesterol ratio than those without mutation (P = 0.03 and 0.02, respectively). For the low density lipoprotein gene defect those with frame shift mutation group showed the worst clinical presentation in terms of low density lipoprotein cholesterol level and cardiovascular frequency.
CONCLUSIONS: There was a statistically significant association between mutations of low density lipoprotein gene and apo lipoprotein B 100 genes and history of cardiovascular disease, younger age of presentation, family history of hyperlipidemia, tendon xanthoma and low density lipoprotein cholesterol level.
Study site: Cardiology Clinic, Hospital Universiti Sains Malaysia (HUSM), Kelantan, Malaysia

Fulltext Analysis of the survival motor neuron and neuronal apoptosis inhibitory protein genes in Malay patients with Spinal Muscular Atrophy

Zilfalil BA, Zabidi-Hussin AMH, Watihayati MS, Rozainah MY, Naing L, Sutomo R, et al.

Med J Malaysia, 2004 Oct;59(4):512-4.

PMID: 15779584 MyJurnal

In Malaysia, Spinal Muscular Atrophy (SMA) is diagnosed based on clinical observation with or without muscle biopsy. Molecular analyses of the SMA-related genes have not been available so far. In this preliminary study, we searched for homozygous deletion of Survival Motor Neuron (SMN1) and Neuronal Apoptosis Inhibitory Protein (NAIP) genes in Malay patients with SMA and found homozygous deletion of SMN1 exon 7 and 8 in all the patients while homozygous deletion of NAIP exon 5 was detected in only our type 1 patients but not in the type 3 patient. To the best of our knowledge, these are the first SMA cases diagnosed at the molecular level in Malaysia.

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

Yahya P, Sulong S, Harun A, Wangkumhang P, Wilantho A, Ngamphiw C, et al.

Int J Legal Med, 2020 Jan;134(1):123-134.

PMID: 31760471 DOI: 10.1007/s00414-019-02184-0

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 FST, informativeness for assignment (In), 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 FST method, while a panel of 200 SNPs selected using In and PCAIMs could be used to identify Malay individuals with an accuracy of approximately 80%.

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

Azman NF, Abdullah WZ, Hanafi S, Diana R, Bahar R, Johan MF, et al.

Ann Hematol, 2020 Apr;99(4):729-735.

PMID: 32078010 DOI: 10.1007/s00277-020-03927-5

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.

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

Osman HA, Hasan H, Suppian R, Hassan S, Andee DZ, Abdul Majid N, et al.

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

PMID: 26422871

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.

Fulltext Chromosomal abnormalities and reproductive outcome in Malaysian couples with miscarriages

Pal S, Ma SO, Norhasimah M, Suhaida MA, Siti Mariam I, Ankathil R, et al.

Singapore Med J, 2009 Oct;50(10):1008-12.

PMID: 19907893

This study was done to determine the prevalence of chromosomal abnormalities and the subsequent reproductive outcome in couples who had two or more miscarriages.

Fulltext Turner syndrome diagnosed in northeastern Malaysia

Kannan TP, Azman BZ, Ahmad Tarmizi AB, Suhaida MA, Siti Mariam I, Ravindran A, et al.

Singapore Med J, 2008 May;49(5):400-4.

PMID: 18465051

Turner syndrome affects about one in 2,000 live-born females, and the wide range of somatic features indicates that a number of different X-located genes are responsible for the complete phenotype. This retrospective study highlights the Turner syndrome cases confirmed through cytogenetic analysis at the Human Genome Centre of Universiti Sains Malaysia, from 2001 to 2006.

Fulltext Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays

Zilfalil BA, Sarina S, Liza-Sharmini AT, Oldfield NJ, Stenhouse SA

Singapore Med J, 2006 Feb;47(2):129-33.

PMID: 16435054

Cystic fibrosis (CF) is one of the common genetic disorders in the western world. It has been reported to be very rare in Asian populations. According to the Cystic Fibrosis Genetic Analysis Consortium, more than 1,000 mutations of the CF gene have been identified. The CF gene, named the cystic fibrosis transmembrane conductance regulator (CFTR), is located on chromosome 7 and composed of 27 exons. This study aims to detect possible CFTR gene mutations in Malays.

Prevalence and Distribution of Major β-Thalassemia Mutations and HbE/β-Thalassemia Variant in Nepalese Ethnic Groups

Lama R, Yusof W, Shrestha TR, Hanafi S, Bhattarai M, Hassan R, et al.

Hematol Oncol Stem Cell Ther, 2022 Mar 01;15(1):279-284.

PMID: 33592169 DOI: 10.1016/j.hemonc.2021.01.004

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.

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.

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