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1.
JCO Glob Oncol ; 10: e2300337, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38271648

ABSTRACT

PURPOSE: Previous studies have reported that cancer incidence trends in Oman varied by tumor site and sex. No comprehensive analysis of all cancer sites had been reported. The objective of this study is to analyze cancer incidence trends in Oman and calculate the annual percent change (APC) in age-standardized rates (ASRs) for all-cancer and 61 individual cancer sites in Omani men and women from 1996 to 2019. METHODS: We gathered incidence data from The Omani National Cancer Registry for all cancers combined and individual tumor sites. We estimated the APC using Poisson regression. RESULTS: The cancer ASR in the Omani population increased by 23% (from 95/100,000 in 1996 to 117.2/100,000 in 2019), with the increase being more pronounced in females (48% v 7% in males). Among the male population, there was significant increase in the ASRs of colon, rectum, thyroid, and prostate cancers, with APCs of 6.92%, 4.24%, 4.19%, and 2.03%, respectively. Among females, all-cancer incidence showed significant increase (APC = 1.39%), and increasing trends were observed in uterine, colon, rectum, thyroid, and breast cancers (APCs = 7.57%, 7.08%, 5.19%, 5.16%, and 4.19%, respectively). CONCLUSION: The ASR of all-cancer increased significantly in Omani women but not in men. Uterine cancer had the highest APC. Colorectal cancer and thyroid ASR increased in both males and females. Breast and prostate cancers showed increasing trends. Further research is needed to explore factors contributing to increasing cancer incidences.


Subject(s)
Breast Neoplasms , Prostatic Neoplasms , Humans , Male , Incidence , Oman/epidemiology , Registries
2.
Acta Biomed ; 94(4): e2023191, 2023 08 03.
Article in English | MEDLINE | ID: mdl-37539594

ABSTRACT

BACKGROUND AND AIM: Beta thalassemia major (ß-TM) is a genetic blood disorder requiring lifelong blood transfusions.  The resulting iron overload damages multiple organs, particularly the heart and endocrine organs. This study aimed to describe and assess the predictors of survival and complications in Omani patients with ß-TM.   Methods: All ß-TM patients registered in the day care of Sultan Qaboos University Hospital were included in this retrospective study.   Results: There were 187 patients with ß-TM with a median follow-up of 24.9 years.  The median ages at diagnosis and the start of chelation were 0.7 and 4.8 years, respectively. The following complications developed at different time points [Median (age in years), Complication Free Probability at 20 years]: Death (20.0 years;85%), hypogonadism (15.9 years;50%), insulin-dependent or non-insulin dependent diabetes (20.0 years;88%), cardiac complications (20.3 years;91%), osteoporosis (20.7 years;96%), hypothyroidism (25.7 years;97%), liver complications (7.3 years;54%). The number of complications predicted death (P = 0.0038). Those born after 1980 had a lower risk of death (P = 0.005), hypogonadism (P = < 0.0001), and cardiac complications (P = 0.004). Higher serum ferritin at the start of chelation was associated with the development of diabetes (P = < 0. 001).   Conclusions: This long-term study shows complications development at different ages, and the number of complications is associated with survival. Later birth cohorts had a lower risk of death, hypogonadism, and cardiac complications. There was a persistent negative impact of delay in the start of iron chelation that is present even after a long follow-up. (www.actabiomedica.it).


Subject(s)
Hypogonadism , Iron Overload , beta-Thalassemia , Humans , Follow-Up Studies , beta-Thalassemia/complications , beta-Thalassemia/therapy , beta-Thalassemia/diagnosis , Retrospective Studies , Iron Overload/complications , Hypogonadism/complications
3.
Clin Immunol ; 252: 109646, 2023 07.
Article in English | MEDLINE | ID: mdl-37209807

ABSTRACT

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a self-limited inflammatory disease of unknown pathogenesis. Familial cases have been described and defects in classical complement components C1q and C4 have been identified in some patients. MATERIAL AND METHODS: We describe genetic and immune investigations of a 16 years old Omani male, a product of consanguineous marriage, who presented with typical clinical and histological features of KFD. RESULTS: We identified a novel homozygous single base deletion in C1S (c.330del; p. Phe110LeufsTer23) resulting in a defect in the classical complement pathway. The patient was negative for all serological markers of SLE. In contrast, two female siblings (also homozygous for the C1S mutation), one has autoimmune thyroid disease (Hashimoto thyroiditis) and a positive ANA and the other sibling has serology consistent with SLE. CONCLUSION: We report the first association between C1s deficiency and KFD.


Subject(s)
Histiocytic Necrotizing Lymphadenitis , Adolescent , Humans , Male , Complement C1s/genetics , Histiocytic Necrotizing Lymphadenitis/genetics , Histiocytic Necrotizing Lymphadenitis/complications , Histiocytic Necrotizing Lymphadenitis/pathology , Loss of Function Mutation
4.
J Clin Immunol ; 43(2): 452-465, 2023 02.
Article in English | MEDLINE | ID: mdl-36324046

ABSTRACT

PURPOSE: Early identification of inborn errors of immunity (IEIs) is crucial due to the significant risk of morbidity and mortality. This study aimed to describe the genetic causes, clinical features, and survival rate of IEIs in Omani patients. METHODS: A prospective study of all Omani patients evaluated for immunodeficiency was conducted over a 17-year period. Clinical features and diagnostic immunological findings were recorded. Targeted gene testing was performed in cases of obvious immunodeficiency. For cases with less conclusive phenotypes, a gene panel was performed, followed by whole-exome sequencing if necessary. RESULTS: A total of 185 patients were diagnosed with IEIs during the study period; of these, 60.5% were male. Mean ages at symptom onset and diagnosis were 30.0 and 50.5 months, respectively. Consanguinity and a family history of IEIs were present in 86.9% and 50.8%, respectively. Most patients presented with lower respiratory infections (65.9%), followed by growth and development manifestations (43.2%). Phagocytic defects were the most common cause of IEIs (31.9%), followed by combined immunodeficiency (21.1%). Overall, 109 of 132 patients (82.6%) who underwent genetic testing received a genetic diagnosis, while testing was inconclusive for the remaining 23 patients (17.4%). Among patients with established diagnoses, 37 genes and 44 variants were identified. Autosomal recessive inheritance was present in 81.7% of patients with gene defects. Several variants were novel. Intravenous immunoglobulin therapy was administered to 39.4% of patients and 21.6% received hematopoietic stem cell transplantation. The overall survival rate was 75.1%. CONCLUSION: This study highlights the genetic causes of IEIs in Omani patients. This information may help in the early identification and management of the disease, thereby improving survival and quality of life.


Subject(s)
Immunologic Deficiency Syndromes , Quality of Life , Male , Humans , Female , Prospective Studies , Genetic Testing , Phenotype , Consanguinity , Immunologic Deficiency Syndromes/genetics
5.
Cancers (Basel) ; 16(1)2023 Dec 20.
Article in English | MEDLINE | ID: mdl-38201450

ABSTRACT

Urogenital cancers, which include prostate, bladder, and kidney malignancies, exert a substantial impact on global cancer-related morbidity and mortality. Proteomic biomarkers, emerging as valuable tools, aim to enhance early detection, prognostic accuracy, and the development of personalized therapeutic strategies. This study undertook a comprehensive systematic review and meta-analysis of the existing literature investigating the role and potential of proteomic biomarkers in plasma, tissue, and urine samples in urogenital cancers. Our extensive search across several databases identified 1879 differentially expressed proteins from 37 studies, signifying their potential as unique biomarkers for these cancers. A meta-analysis of the significantly differentially expressed proteins was executed, accentuating the findings through visually intuitive volcano plots. A functional enrichment analysis unveiled their significant involvement in diverse biological processes, including signal transduction, immune response, cell communication, and cell growth. A pathway analysis highlighted the participation of key pathways such as the nectin adhesion pathway, TRAIL signaling pathway, and integrin signaling pathways. These findings not only pave the way for future investigations into early detection and targeted therapeutic approaches but also underscore the fundamental role of proteomics in advancing our understanding of the molecular mechanisms underpinning urogenital cancer pathogenesis. Ultimately, these findings hold remarkable potential to significantly enhance patient care and improve clinical outcomes.

6.
Acta Biomed ; 93(2): e2022022, 2022 05 11.
Article in English | MEDLINE | ID: mdl-35546036

ABSTRACT

BACKGROUND AND AIM OF THE WORK: Cardiac complications occur in patients with non-transfusion dependent thalassemia (NTDT). The study aimed to evaluate transfusion effect on systolic and diastolic cardiac function in young NTDT patients.  Methods:  Study design: Cohort study. Seventeen regularly-transfused patients with NTDT (12.5±5.3 years; group 1) and 15 none/minimally transfused patients (13.2±4.8 years; group 2) were followed up for 5 years and compared as regards their clinical parameters, echocardiographic and Tissue-Doppler-Imaging. RESULTS: Group 2 patients had significantly higher peak late-diastolic velocity of the left-ventricular-inflow Doppler (Am). Mitral-valve A-wave duration/pulmonary-veins, A-wave duration-ratio and pulmonary-vein S/D velocities-ratio were larger in group 2 as well (p = < 0.01). The diameters of right and left outflow-tract were larger with a higher cardiac-index in patients of group 2. Systolic-function was similar in the 2 studied groups. CONCLUSION: Diastolic function assessment revealed indicators of an abnormal relaxation of left-ventricle in non-transfused patients, which suggests a diastolic dysfunction. An increase in the diameter of the outflow-tract is likely attributed to high cardiac-output status in non-transfused NTDT patients as they have a higher cardiac index. Early start of regular transfusion for NTDT patients might prevent serious long-term cardiac complications.


Subject(s)
Echocardiography, Doppler , Thalassemia , Child , Cohort Studies , Diastole , Echocardiography , Humans , Thalassemia/complications , Thalassemia/therapy , Ventricular Function, Left
7.
Ther Drug Monit ; 44(4): 527-534, 2022 08 01.
Article in English | MEDLINE | ID: mdl-34990437

ABSTRACT

BACKGROUND: Busulfan (Bu) is an alkylating drug used in many preparative regimens before hematopoietic stem cell transplantation (HSCT). It is conjugated in the liver mainly by glutathione S-transferase isoenzyme A1-1 ( GSTA1 ). Genetic polymorphisms in these isoenzymes may affect the pharmacokinetics of Bu and the clinical outcomes of HSCT. This study aimed to assess the impact of glutathione S-transferase ( GST ) genetic polymorphisms on the clearance of Bu and the clinical outcomes of patients undergoing HSCT. METHODS: This single-center retrospective study included patients who received IV Bu before HSCT at Sultan Qaboos University Hospital (SQUH), Oman from January 2003 to October 2016. Genotyping for polymorphisms was performed for GSTM1 , GSTT1 , GSTA1 , and GSTP1 . Each GST polymorphism was analyzed for its impact on Bu clearance and HSCT outcomes. RESULTS: A total of 135 patients were included. The mean Bu clearance was 3.7 ± 0.98 mL/min/kg. Patients with GSTA1 A-513G heterozygosity (AG) were found to have a higher incidence of graft loss ( P = 0.006). Homozygous double null of GSTM1 and GSTT1 was associated with a higher incidence of acute graft versus host disease ( P = 0.04). Double non-null GSTM1 and GSTT1 and non-null GSTM1 increased the risk of mortality ( P = 0.034 and 0.021, respectively). CONCLUSIONS: GST genotyping before HSCT may predict HSCT outcomes. The results of this preliminary retrospective study need to be confirmed in a larger prospective study.


Subject(s)
Busulfan , Hematopoietic Stem Cell Transplantation , Busulfan/pharmacokinetics , Busulfan/therapeutic use , Genotype , Glutathione Transferase/genetics , Hematopoietic Stem Cell Transplantation/methods , Humans , Polymorphism, Genetic/genetics , Prospective Studies , Retrospective Studies , Transplantation Conditioning/methods
8.
Vox Sang ; 117(3): 424-430, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34647328

ABSTRACT

BACKGROUND AND OBJECTIVES: Blood group genotyping has been used in different populations. This study aims at evaluating the genotypes of common blood group antigens in the Omani blood donors and to assess the concordance rate with obtained phenotypes. MATERIAL AND METHODS: Blood samples from 180 Omani donors were evaluated. Samples were typed by serological methods for the five blood group systems MNS, RH (RHD/RHCE), KEL, FY and JK. Samples were genotyped using RBC-FluoGene vERYfy eXtend kit (inno-train©). Predicted phenotypic variants for 70 red blood cell antigens among the MNS, RH (RHD/RHCE), KEL, FY, JK, DO, LU, YT, DI, VEL, CO and KN blood group systems were assessed. RESULTS: Simultaneous phenotype and genotype results were available in 130 subjects. Concordance rate was >95% in all blood group systems with exception of Fy(b+) (87%). Homozygous GATA-1 mutation leading to erythroid silencing FY*02N.01 (resulting in the Fy(b-)ES phenotype) was detected in 81/112 (72%) of genotyped samples. In addition, discrepant Fyb phenotype/genotype result was obtained in 14/112 samples; 13 of which has a heterozygous GATA-1 mutation and one sample with a wild GATA genotype. D and partial e c.733C>G variants expressing the V+VS+ phenotype were found in 22/121 (18.2%) and 14/120 (11.7%) of the samples, respectively. Di(a-b+), Js(a-b+), Yt(a+b-) and Kn(a+b-) genotype frequencies were 99.4%, 95.8%, 91.9% and 97.7%, respectively. CONCLUSION: In conclusion, we report a high frequency of FY*02N.01 allele due to homozygous c.-67T>C GATA-1 single-nucleotide variation. This is the first study reporting the detailed distribution of common and rare red cell genotypes in Omani blood donors.


Subject(s)
Blood Group Antigens , Alleles , Blood Donors , Blood Group Antigens/genetics , Genotype , Humans , Phenotype
9.
Clin Immunol ; 210: 108308, 2020 01.
Article in English | MEDLINE | ID: mdl-31726101

ABSTRACT

Invariant natural killer T (iNKT) cells are being considered as potential targets for immunotherapeutic strategies in a variety of conditions including sickle cell disease (SCD). However, relatively little is known about the fate of iNKT cell subsets in children with SCD. Herein, quantitative and qualitative analyses of circulating iNKT cell subsets were carried out in 120 children in steady state and 30 healthy controls. Children with SCD displayed significantly elevated levels of circulating iNKT cell subsets with a preferential polarization toward Th2-like cells. The known SCD modifiers did not influence levels of iNKT cell subsets, except that children carrying the Bantu haplotype exhibited elevated levels of CD4iNKT cells, and to a lesser degree CD8iNKT cells. Collectively, these findings indicate that circulating iNKT cell subsets are significantly increased in children with SCD, and highlight the existence of imbalanced production of cytokines toward Th2-like phenotype, which seems to be associated with genetic polymorphisms.


Subject(s)
Anemia, Sickle Cell/immunology , Natural Killer T-Cells/immunology , T-Lymphocyte Subsets/immunology , Adolescent , Anemia, Sickle Cell/genetics , Blood Circulation , CD4 Antigens/metabolism , CD8 Antigens/metabolism , Cell Count , Child , Child, Preschool , Cross-Sectional Studies , Cytokines/metabolism , Female , Flow Cytometry , Haplotypes , Humans , Male , Th2 Cells/immunology
10.
J Clin Pathol ; 71(4): 303-308, 2018 Apr.
Article in English | MEDLINE | ID: mdl-28784617

ABSTRACT

OBJECTIVES: To describe the laboratory features of haemoglobin Fontainebleau (Hb FB) and its interactions with various α and ß globin gene mutations in the Omani population. METHODS: Over a period of 10 years, a total of 94 blood samples were suspected to have an α variant on HPLC at the Sultan Qaboos University Hospital, Muscat, Oman. Molecular testing was performed using PCR based techniques to define the variant and to analyse other interacting mutations in either α or ß globin genes. RESULTS: Of 94 subjects, molecular analysis confirmed the Hb FB variant in 55 samples (38 non-cord and 17 cord blood). A total of 36/38 non-cord samples were heterozygous for the variant, while all 17 cord blood samples were heterozygotes. A total of 43/55 individuals had a concomitant α and/or ß globin gene mutation. CONCLUSIONS: Hb FB is the the most common α variant in the Omani population. We report the different HPLC profiles of this variant that we observed, with and without other haemoglobinopathies in non-cord and cord blood samples. This is the first report describing the HPLC profiles of this α globin chain variant on 1 year follow-up testing of cord blood samples. With careful analysis by HPLC, it is possible not only to identify Hb FB but also to predict any concomitant α and/or ß globin gene mutations.


Subject(s)
Hemoglobinopathies/genetics , Hemoglobins, Abnormal/genetics , Hemoglobinopathies/blood , Humans , Mutation , Oman
11.
Acta Haematol ; 138(3): 175-181, 2017.
Article in English | MEDLINE | ID: mdl-29065396

ABSTRACT

BACKGROUND/AIMS: In CD34-positive acute myeloid leukaemia (AML), the leukaemia-initiating event likely takes place in the CD34+CD38- cell compartment. CD123 has been shown to be a unique marker of leukaemic stem cells within the CD34+CD38- compartment. The aim of this study was to identify the percentage of CD34+CD38-CD123+ cells in AML blasts, AML CD34+CD38- stem cells, and normal and regenerating bone marrow CD34+CD38- stem cells from non-myeloid malignancies. METHODS: Thirty-eight adult de novo AML patients with intention to treat were enrolled after the application of inclusion criteria from February 2012 to February 2017. The percentage of the CD34+CD38-CD123+ phenotype in the blast population at diagnosis was determined using a CD45-gating strategy and CD34+ backgating by flow cytometry. We studied the CD34+CD38-CD123+ fraction in AML blasts at diagnosis, and its utility as a unique phenotype for minimal residual disease (MRD) of AML patients. RESULTS: CD123+ cells were present in 97% of AML blasts in patients at diagnosis (median 90%; range 21-99%). CD123+ cells were also present in 97% of the CD34+CD38- compartment (median 0.8164%, range 0.0262-39.7%). Interestingly, CD123 was not present in normal and regenerating CD34+CD38- bone marrow stem cells (range 0.002- 0.067 and 0.004-0.086, respectively). CONCLUSION: The CD34+CD38-CD123+ phenotype is present in virtually all AML blasts and it may be used as a unique single phenotype for MRD detection in AML patients.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , Antigens, CD34/metabolism , Bone Marrow/metabolism , Interleukin-3 Receptor alpha Subunit/metabolism , Leukemia, Myeloid, Acute/diagnosis , Neoplasm, Residual/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Bone Marrow/pathology , Bone Marrow/physiology , Female , Flow Cytometry , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Neoplasm, Residual/pathology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nucleophosmin , Phenotype , Polymorphism, Genetic , Young Adult , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism
13.
Mediterr J Hematol Infect Dis ; 8(1): e2016013, 2016.
Article in English | MEDLINE | ID: mdl-26977272

ABSTRACT

OBJECTIVES: Our aim was to study mannose-binding protein (MBP) polymorphisms in exonic and promoter region and correlate it with associated infections and vasoocculsive (VOC) episodes in sickle cell disease (SCD) patients since MBP plays an important role in innate immunity by activating the complement system. METHODS: We studied the genetic polymorphisms in the Exon 1 (alleles A/O) and promoter region (alleles Y/X; H/L, P/Q) of the MBL2 gene, in SCD patients as an increased incidence of infections is seen in these patients. A PCR-based, targeted genomic DNA sequencing of MBL2 was used to study 68 SCD Omani patients and 44 controls (healthy voluntary blood donors). RESULTS: In SCD patients, the frequency of the genotype related to the high production of MBL was 0.35 (YA/YA) and for intermediate/low production was 0.65 (YA/XA, XA/XA, YA/YO, XA/YO, YO/YO). The observed frequencies of MBL2 gene promoter polymorphism (-221, Y/X) were 44.4% and 20.5% for the heterozygous genotype Y/X and 3.2% and 2.2% for the homozygous (X/X) respectively between SCD patients and controls. MBL2 Exon1 gene mutations were 29.4% and 50% for the heterozygous genotype A/O and 5.9% and 6.8% respectively for the homozygous (O/O) genotype between SCD patients and controls. The distribution of variant MBL2 gene polymorphisms did not show any correlation in SCD patients with or without VOC attacks (p=0.16; OR -0.486; CI=0.177 -1.33), however, it was correlated with infections (p=0.0162; OR -3.55; CI 1.25-10.04). CONCLUSIONS: Although the frequency of the genotypes and haplotypes of MBL2 in SCD patients did not differ from controls, overall in the SCD patient cohort the increased representation of variant alleles was significantly correlated with infections (p<0.05). However, these variant MBL2 polymorphisms did not seem to play a significant role in the VOC episodes in this SCD cohort.

14.
Mediterr J Hematol Infect Dis ; 7(1): e2015060, 2015.
Article in English | MEDLINE | ID: mdl-26543529

ABSTRACT

BACKGROUND: We explored the potential relationship between steady state serum bilirubin levels and the incidence of cholelithiasis in the context of UGT1A1 gene A(TA)nTAA promoter polymorphism in Omani sickle cell anemia (SCA) patients, homozygotes for African (Benin and Bantu) and Arab-Indian ß(S) haplotypes, but sharing the same microgeographical environment and comparable life style factors. METHODS: 136 SCA patients were retrospectively studied in whom imaging data including abdominal CT scan, MRI or Ultrasonography were routinely available. Available data on the mean steady state hematological/biochemical parameters (n=136), ß(s) haplotypes(n=136), α globin gene status (n=105) and UGT1A1 genotypes (n=133) were reviewed from the respective medical records. RESULTS: The mean serum total bilirubin level was significantly higher in the homozygous UGT1A1(AT)7 group as compared to UGT1A1(AT)6 group. Thus, not cholelithiasis but total serum bilirubin was influenced by UGT1A1 polymorphism in this SCA cohort. CONCLUSION: As observed in other population groups, the UGT1A1 (AT)7 homozygosity was significantly associated with raised serum total bilirubin level, but the prevalence of gallstones in the Omani SCA patients was not associated with α thalassaemia, UGT1A1 polymorphism, or ß(s) haplotypes.

15.
J Pediatr Hematol Oncol ; 36(4): e248-50, 2014 May.
Article in English | MEDLINE | ID: mdl-24072239

ABSTRACT

BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare, autosomal, recessive lysosomal disorder with hematological and immunologic abnormalities; however, stem-cell transplantation from a matched or related donor may be curative. Many mutations of the CHS1/LYST gene have been reported to date. We report a novel nonsense mutation of the CHS1/LYST gene in 3 Omani patients. METHODS AND RESULTS: Three patients from 2 different families presented with clinical and laboratory features of CHS and a history of death of a previous sibling because of a severe illness, suggestive of the accelerated phase of CHS. Giant granules were present in the myeloid cell lines. Before the stem-cell transplant, the first patient underwent gene sequencing of all exons of the lysosome trafficking regulator (CHS1/LYST) gene and revealed a nonsense mutation in exon 5 (c.925C>T, p.R309X). Subsequently, upon presentation, the second and third patients' direct gene sequencing of exon 5 revealed the same mutation. CONCLUSIONS: We report a nonsense mutation in exon 5 (c.925C>T, p.R309X). This supports the allelic heterogeneity of CHS and is in line with most reported mutation types that lead to a truncated protein. Identification of the mutation type will facilitate timely diagnosis, management, and family counseling for those with affected children in Oman.


Subject(s)
Chediak-Higashi Syndrome/genetics , Codon, Nonsense , Exons , Vesicular Transport Proteins/genetics , Allografts , Chediak-Higashi Syndrome/therapy , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Male , Oman , Stem Cell Transplantation
16.
Pediatr Blood Cancer ; 61(3): 528-31, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24249281

ABSTRACT

BACKGROUND: Thiamine responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type 1 diabetes mellitus and sensorineural deafness. Other clinical findings have been described in few cases. The SLC19A2 gene on chromosome 1q 23.3 is implicated in all cases with TRMA. Our aim is to discuss the clinical manifestations of all Omani children diagnosed with TRMA and determine genotype-phenotype relationship. PROCEDURE: Clinical and laboratory data of all patients diagnosed in Oman were retrospectively collected. Mutation analysis of affected families was conducted using two Microsatellite markers. Genotyping was performed with fluorescent-labeled PCR primers. To define the deletion breakpoint region, PCR reactions were carried out using different primer pairs located at the introns 3 and 3'-untranslated region with Expand Long Template PCR kit. RESULTS: A total of six children have been diagnosed with this syndrome. They were five females and one male. They all presented with sensorineural deafness at birth while the age of anemia presentation ranged between 6 weeks to 19 months. They all belong to same family with complex interfamilial marriages and presented with the typical triad. Of interest is the very rare presentation of one patient with Uhl cardiac anomaly (total absence of right ventricular myocardium with apposition of endocardium and pericardium) that has never been described before in patients with TRMA. All patients have a novel large deletion of 5,224 bp involving exons 4, 5, and 6 of SLC19A2. CONCLUSIONS: TRMA is a disease of expanding phenotypic spectrum with poor genotype-phenotype correlation.


Subject(s)
Anemia, Megaloblastic/genetics , Diabetes Mellitus/genetics , Hearing Loss, Sensorineural/genetics , Thiamine/therapeutic use , Anemia, Megaloblastic/drug therapy , Female , Humans , Infant , Male , Mutation , Phenotype , Retrospective Studies
17.
Int J Hematol ; 98(2): 240-2, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23797957

ABSTRACT

We report the presence of two different dglobin gene mutations causing d?-thalassemia in association with homozygous (-a3.7/-a3.7) genotype for the first time in an Omani child with a low hemoglobin A2 (HbA2) of 0.8 %. Direct nucleotide sequencing revealed compound heterozygote mutations in the patient's d-globin genes: HbA2-Yialousa (HBD: c.82G[C) and HbA2- Wrens (HBD: c.295G[A). In Oman, where a and b-thalassemia and HbS are prevalent, an awareness of the presence of different d-globin gene mutations is important as complex interactions between these hemoglobinopathies can lead to the misdiagnosis of b-thalassemia carriers.


Subject(s)
Hemoglobins, Abnormal/genetics , Heterozygote , delta-Thalassemia/genetics , Child, Preschool , DNA Mutational Analysis , Humans , Male , Oman
19.
J Hum Genet ; 57(10): 665-9, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22854539

ABSTRACT

The objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G>A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R(2)=0.45).


Subject(s)
Algorithms , Pharmacogenetics/methods , Warfarin/administration & dosage , Adult , Aged , Aryl Hydrocarbon Hydroxylases/genetics , Atrial Fibrillation/drug therapy , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System/genetics , Cytochrome P450 Family 4 , Drug Dosage Calculations , Ethnicity/genetics , Female , Genetic Association Studies , Genetic Loci , Genetics, Population/methods , Genotype , Humans , Linear Models , Linkage Disequilibrium , Male , Middle Aged , Mixed Function Oxygenases/genetics , Oman/ethnology , Polymorphism, Genetic , Prospective Studies , Venous Thrombosis/drug therapy , Vitamin K Epoxide Reductases
20.
Hum Biol ; 84(1): 67-77, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22452429

ABSTRACT

This is the first study to evaluate the spectrum and prevalence of dose-predictive genetic polymorphisms of the CYP2C9, CYP4F2 and VKORC1 loci together, in a geographically defined, ethnically admixed healthy adult Omani population sharing common lifestyle/environmental factors. Since the present-day Omani population is the result of an admixture of Caucasian, African and Asian ancestries, we compared the pharmacogenetic profile of these three loci in this population. Interestingly, the Omani pharmacogenetic profile, in terms of allele and genotype distribution, has values that are intermediate between Caucasians and African Americans, the African admixture further substantiated by the presence of the CYP2C9*8 allele. However, limitations and usefulness of such comparisons warrant caution, as the data from pharmacogenetic literature do not always represent bona fide population categories. Furthermore, definition of study population based on microgeographical scale would be more appropriate in pharmacogenetic research rather than the flawed racial, ethnic, or social categorizations since pharmacogenetic variation is clinal, and genetic influences will be further altered by lifestyle and environmental factors.


Subject(s)
Anticoagulants/pharmacology , Aryl Hydrocarbon Hydroxylases/genetics , Cytochrome P-450 Enzyme System/genetics , Mixed Function Oxygenases/genetics , Warfarin/pharmacology , Adult , Aryl Hydrocarbon Hydroxylases/metabolism , Chi-Square Distribution , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Female , Gene Frequency , Genotype , Humans , Male , Mixed Function Oxygenases/metabolism , Oman , Polymorphism, Genetic , Prevalence , Vitamin K Epoxide Reductases
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