Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability.

Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system.

TLR2, TLR4 and CD86 gene polymorphisms in recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is an inflammatory disease induced by genetic and environmental factors. Toll-like receptor (TLR) and CD86 are essential components for innate immunity and cellular immune response. We aimed to determine whether inheritance of specific TLR2, TLR4and CD86 gene polymorphisms are associated with RAS. METHODS: Ninety-six patients with RAS and 153 controls were studied. Eight SNPs were genotyped using PCR-RFLP technique; four in TLR2 gene: rs4696480, rs3804100, rs121917864, rs5743708; three in TLR4 gene: rs10759931, rs4986790 rs1927911; and one in CD86 gene rs17281995. Association was assessed by logistic regression analysis. Linkage disequilibrium (LD) was assessed using the Haploview program. RESULTS: Significant increase in inheritance of A allele (OR = 1.6, P = 0.01) and AA genotype (OR = 3.89, P = 0.01) of TLR4 rs10759931 was observed in cases. TLR4rs1927911 C allele and CC genotype were also increased (OR = 1.60 and 2.78 respectively); however, this was not statistically significant (P = 0.02 and 0.03 respectively). TLR2 and CD86 did not show association with RAS. CONCLUSIONS: This is the first study to investigate the association of TLR and CD86 with RAS. We found a significant association between TLR4 rs10759931 polymorphism and RAS. Confirmatory studies in other populations and functional investigations are needed to determine the role of TLR4 in RAS.

Association of cell adhesion molecule gene polymorphisms with recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral ulcerative condition. At ulcer sites vascular adhesion molecule-1 (VCAM-1), E-selectin and intercellular adhesion molecule-1 (ICAM-1) are strongly expressed on blood vessels, and ICAM-1 is expressed on keratinocytes. Expression of these molecules would promote leukocyte accumulation and invasion of the epithelium. Thus, polymorphisms in these candidate genes might contribute to RAS susceptibility. We investigated whether the inheritance of specific selectin, ICAM and VCAM gene polymorphisms is associated with RAS susceptibility. METHODS: Ninety-six RAS cases and 153 controls were recruited from a Jordanian population. Blood was collected for hematological investigations and genotyping. Six SNPs were genotyped: E-selectin rs5361 and rs1805193, L-selectin, rs2205849, ICAM-1 rs5498, ICAM-5 rs885743 and VCAM-1 rs1800821. Association was determined using chi-square and binary logistic regression analysis after correcting for confounding factors. Linkage disequilibrium was determined using the EH program, and the Phase 2.1 program was used to construct and compare haplotypes between cases and controls. RESULTS: There was a significant association of the A allele (Pcorr  = 0.027), AA and AC genotypes (OR = 10.9 and 9.0, respectively) of the E-selectin rs5361 gene polymorphism and TAA haplotype (rs2205849, rs5361, and rs1805193, respectively; P = 0.03) with RAS. None of the other SNPs showed a significant association. CONCLUSIONS: This is the first report to link inheritance of the A allele, AA and AC genotypes of the E-selectin rs5361 polymorphism with increased risk of RAS. Further studies in different patient cohorts are needed to confirm the association, and functional analyses might clarify the biological significance of the association.

Protein contact map prediction using multi-stage hybrid intelligence inference systems.

Proteins are one of the most important molecules in organisms. Protein function can be inferred from its 3D structure. The gap between the number of discovered protein sequences and the number of structures determined by the experimental methods is increasing. Accurate prediction of protein contact map is an important step toward the reconstruction of the protein's 3D structure. In spite of continuous progress in developing contact map predictors, highly accurate prediction is still unresolved problem. In this paper, we introduce a new predictor, JUSTcon, which consists of multiple parallel stages that are based on adaptive neuro-fuzzy inference System (ANFIS) and K nearest neighbors (KNNs) classifier. A smart filtering operation is performed on the final outputs to ensure normal connectivity behaviors of amino acids pairs. The window size of the filter is selected by a simple expert system. The dataset was divided into testing dataset of 50 proteins and training dataset of 450 proteins. The system produced an average accuracy of 45.2% for the sequence separation of six amino acids. In addition, JUSTcon outperformed SVMcon and PROFcon predictors in the cases of large separation distances. JUSTcon produced an average accuracy of 15% for the sequence separation of 24 amino acids after applying it on CASP9 targets.

Immunohistochemical expression of substance P in breast cancer and its association with prognostic parameters and Ki-67 index.

BACKGROUND: The neuropeptide substance P is a potential biomarker and therapeutic target in cancer. The main objectives of this study were to investigate the expression level of substance P in different breast cancer molecular subtypes and identify its association with clinicopathological parameters of patients and with Ki-67 index. METHODS: A retrospective analysis was performed for a total of 164 paraffin-embedded breast cancer tissue samples [42 Her2/neu-enriched, 40 luminal A, 42 luminal B (triple-positive) and 40 triple negative subtypes]. The tissue microarray slides containing specimens were used to determine the expression of substance p and Ki-67 by immunohistochemical staining. RESULTS: The mean age of the cohort was 51.35 years. Twenty two percent of cases had low substance P expression levels (TS ≤ 5), while 78% had high expression levels (TS > 5). A significant association was found between SP expression level and breast cancer molecular subtype (p = 0.002), TNM stage (p = 0.034), pN stage (p = 0.013), axillary lymph node metastasis (p = 0.004), ER and PR statuses (p<0.001) and history of DCIS (p = 0.009). The average percentage of Ki-67 expression was 27.05%. When analyzed as a continuous variable, significant differences were observed between the mean Ki-67 scores and molecular subtype (p = 0.001), grade (p = 0.003), pN stage (p = 0.007), axillary lymph node metastasis (p = 0.001), and ER and PR statuses (p <0.001). CONCLUSION: SP is overexpressed in most of the analyzed tissues and has a negative prognostic value in the breast cancer patients. Besides substance P is a potential therapeutic target in breast cancer.

SMOC2 gene variant and the risk of vitiligo in Jordanian Arabs.

Generalized vitiligo is a common autoimmune disorder, characterized by patchy loss of pigmentation due to melanocyte death. It is a multifactorial disorder in which multiple genes and environmental triggers contribute to the expression of the phenotype. Different genetic variants can have varying effects on having vitiligo. Recently, an SMOC2 variant (rs13208776) was reported to be associated with vitiligo in Caucasian patients from an isolated founder population. In this study, we investigate the association of SMOC2 variant with Jordanian Arab vitiligo patients. Forty-four patients with generalized vitiligo and 151 matched normal controls were recruited. DNA samples were obtained from patients and controls and samples were genotyped for SMOC2 variant by restriction fragment length polymorphism. Allelic frequency of the less common allele (A allele) was 29.5% in patients compared to 19.6% in the controls (p = 0.27). Genotypic frequency for AA was 4.5% in patients and 7.9% in controls while heterozygous genotypes were 50% for patients and 33.1% in controls. Genotypes did not show statistical difference in patients versus control (p = 0.12). Our data shows that the variant rs13208776 in SMOC2 gene does not play a major role in increasing the risk of vitiligo in Jordanian Arab patients. This is in contrast to the previous association reported for Caucasian patients from an isolated patient population in Romania. This signifies genetic differences in the two populations.

A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing.

Intellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

Human and mouse disorders of pigmentation.

Disorders of pigmentation were among the first genetic diseases ever recognized because of their visually striking clinical phenotypes, resulting from defects of pigmentary melanocytes. Recent years have seen remarkable progress in understanding these diseases, largely as a result of the systematic parallel study of human patients and inbred mice with similar phenotypes. Our understanding of disorders of pigmentation indicates that these diseases may be most usefully considered as abnormalities of melanocyte development, function, or survival.

Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli.

Deficiency of propionyl-CoA carboxylase (PCC) results in propionic acidemia, an autosomal recessive disorder characterized by ketoacidosis sufficiently severe to cause neonatal death. PCC is involved in the catabolism of branched-chain amino acids, odd-chain fatty acids, and cholesterol. The enzyme is a biotin-dependent mitochondrial protein composed of two heterologous subunits arranged into an 800-kDa alpha(6 )beta(6) dodecameric structure. Approximately 60 mutations have been reported in the nuclear genes PCCA and PCCB that encode the two PCC subunits. The vast majority of these mutations have not been examined at the protein level. We present an initial characterization of 13 mutations located in exons 1, 3-7, and 12-14 of PCCB. After expression in E. coli, these recombinant mutant enzymes were analyzed for stability, biotinylation, alpha-beta subunit interaction, and activity. Our results show a functional dichotomy in these PCCB mutations with some mutants (R44P, S106R, G131R, G198D, V205D, I408del, and M442T) capable of varying degrees of assembly but forming catalytically inactive PCC proteins. Other PCCB mutants (R165W, E168K, D178H, P228L, and R410W) that are PCC deficient in patient-derived fibroblasts, were found to be capable of expressing wild-type level PCC activity when assembled in our chaperone-assisted E. coli expression system. This result indicates that these mutations exert their pathogenic effect due to an inability to assemble correctly in patients' cells. This initial screen has identified a range of mutant PCC proteins that are sufficiently stable to be purified and subsequently used for structure-function analysis to further elucidate the complex relationship between genotype and phenotype in propionic acidemia.

DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.

Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

Polymorphisms in NLRP1 gene and susceptibility to autoimmune thyroid disease.

The autoimmune thyroid disorders, or AITDs, comprise 2 related disorders, Graves' disease and Hashimoto thyroiditis. In AITD, immune system produces antibodies against autothyroid antigens. The etiology of AITDs involves a complex interaction between genetic predisposing factors and environmental triggering factors. Variations in NACHT leucine-rich repeat protein 1(NLRP1) gene a key regulator of the innate immunity have been shown to confer risk for vitiligo and several autoimmune diseases. In this study we hypothesize that variants in NLRP1 gene might be involved in the susceptibility to autoimmune thyroid disease. Five single nucleotide polymorphisms (SNPs) in NLRP1 were genotyped in 207 AITD patients and 220 normal controls. We found that NLRP1 rs12150220 T allele (OR = 1.273, 95% CI: 0.971-1.670, p = 0.040) and NLRP1 rs2670660 G allele (OR = 1.264, 95% CI: 0.965-1.656, p = 0.044) were significantly associated with AITD compared with controls. These results suggest that NLRP1 may be involved in the pathogenesis of AITD.

Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the Jordanian Arab population.

Autoimmune thyroid diseases (AITDs) (Hashimoto thyroiditis and Graves' disease) are complex polygenic disorders with multiple genes thought to contribute to the risk of disease. The contribution of these genes differs by different populations. The PTPN22 gene is reported to be associated with multiple autoimmune diseases, but results of association are conflicting in different populations. The SMOC2 gene is reported to be associated with families with autoimmune vitiligo that had other autoimmunities including thyroid disease. The study aims to investigate the association of PTPN22 and SMOC2 single nucleotide polymorphisms with thyroid disease in a cohort of Jordanian patients. We collected blood samples from 204 thyroid patients and 216 normal controls. We used PCR-RFLP to genotype rs2476601 in PTPN22 and rs13208776 in SMOC2 genes. Both of the SNPS did not show significant association with thyroid disease, even after stratification according to subtype of disease (Hashimoto thyroiditis and Graves' disease) or gender. We reanalyzed SMOC2 SNP using a dominant and recessive models and we got marginal significance when using a dominant model with female-only patients (P = 0.052). PTPN22 SNP did not show association with autoimmune thyroid disease in our patient cohort. This may be due to the low frequency of this SNP in the Jordanian population. SMOC2 SNP, on the other hand, may play a role in AITD susceptibility as a dominant polymorphism. Additional samples might be needed to confirm or exclude association of SMOC2 with AITD.

Genetic association of adiponectin with type 2 diabetes in Jordanian Arab population.

Adiponectin, a protein exclusively secreted by adipose tissue and present at low levels in obese individuals, is now widely recognized as a key determinant of insulin sensitivity and protection against obesity-associated metabolic syndrome. In Jordan, prevalence of diabetes (17.1%) is twice that of the United States (7.8%). In this study, we examined the contribution of the promoter variant rs266729 (-11377C>G) of the ADIPOQ gene as a risk factor for diabetic patients in Jordan. DNA was extracted from blood samples for patients and controls .Polymerase chain reaction and restriction fragment length polymorphism were used to genotype this variant. A total of 420 type 2 diabetic patients and 230 controls were successfully genotyped. The results showed a significant genotypic (p=0.00001) and allelic (p=0.01) association with variant in the diabetic patients as compared to controls. This suggests that the ADIPOQ gene plays a major role in increasing the risk of diabetes, at least in the Jordanian Arab population.

Atorvastatin treatment modulates the interaction between leptin and adiponectin, and the clinical parameters in patients with type II diabetes.

The aim of this study was to examine the effect of atorvastatin treatment on levels of leptin, adiponectin and insulin resistance, and their correlation with clinical parameters, in patients with type II diabetes. Patients with diabetes (n=394) were divided into two groups, comprising 161 patients who received 20 mg/day atorvastatin (statin group), and 233 patients who did not receive statins (statin-free group). The results showed that atorvastatin treatment of patients with diabetes was not associated with changes in leptin, adiponectin, the leptin/adiponectin (L/A) ratio or homeostasis model assessment-insulin resistance (HOMA-IR). However, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and total cholesterol (Tchol) were positively correlated with leptin and L/A ratio in the statin group only (P<0.05). By contrast, high-density lipoprotein cholesterol (HDL-C) showed a significant positive correlation with adiponectin in the statin and statin-free groups (P<0.05). Additionally, a positive correlation was found between HOMA-IR and glycated hemoglobin (HbA1c), and TG, in both groups, whereas Tchol was positively correlated with HOMA-IR in the statin group only (P<0.05). When multivariate analysis was performed with HOMA-IR as the dependent variable, and with adjustment for age, body mass index (BMI) and waist circumference, HbA1c was found to be a significant predictor of HOMA-IR or insulin resistance. In conclusion, atorvastatin treatment may have several effects on the interaction between leptin and adiponectin, and on clinical parameters in patients with type II diabetes.

CDKL5 and ARX mutations in males with early-onset epilepsy.

Mutations in CDKL5 and ARX are known causes of early-onset epilepsy and severe developmental delay in males and females. Although numerous males with ARX mutations associated with various phenotypes have been reported in the literature, the majority of CDKL5 mutations have been identified in females with a phenotype characterized by early-onset epilepsy, severe global developmental delay, absent speech, and stereotypic hand movements. To date, only 10 males with CDKL5 mutations have been reported. Our retrospective study reports on the clinical, neuroimaging, and molecular findings of 18 males with early-onset epilepsy caused by either CDKL5 or ARX mutations. These 18 patients include eight new males with CDKL5 mutations and 10 with ARX mutations identified through sequence analysis of 266 and 346 males, respectively, at our molecular diagnostic laboratory. Our large dataset therefore expands on the number of reported males with CDKL5 mutations and highlights that aberrations of CDKL5 and ARX combined are an important consideration in the genetic forms of early-onset epilepsy in boys.

Human metapneumovirus in Jordan: prevalence and clinical symptoms in hospitalized pediatric patients and molecular virus characterization.

Respiratory viral infections account for significant morbidity and mortality especially in young children worldwide. Human metapneumovirus (hMPV) causes illnesses ranging from mild respiratory problems to bronchiolitis and severe pneumonia. From January to December 2007, 220 nasopharyngeal aspirates were collected from children younger ≤ 13 years old hospitalized with lower respiratory tract infection to detect hMPV by revese transcription-polymerase chain reaction and to clone and sequence the hMPV-positive samples. Human metapneumovirus was detected in 28 (12.7%) specimens with a median age of 7 months (range 1.3 to 24 months). Human metapneumovirus type A and type B were detected in 26 (93%) and 8 (28.6%) of specimens, respectively. Coinfection with hMPV type A and type B was detected in 6 (21.4%) specimens positive for hMPV. The major clinical diagnosis of hMPV-positive patients was bronchiolitis (75%). Human metapneumovirus and hMPV type B were found to be significantly associated with bronchiolitis (P = 0.03 and 0.01, respectively). Human metapneumovirus and hMPV type A were found to be significantly associated with pneumonia (P = 0.004 and 0.002, respectively). The main symptoms in patients infected with hMPV were cough (92.9%), fever (82.1%), and wheezing (78.6%), with a significant association of hMPV type A with fever (P = 0.018). Human metapneumovirus was seasonally distributed; most infections with hMPV were reported in the late winter and early spring. The peak of hMPV incidence was in February (10/28; 35.7%). Sequencing of purified plasmid DNA was performed in forward and reverse direction to confirm the results of hMPV-positive samples which scored 97% identity to hMPV type A genome isolate NL/17/00 and showing C-T variation that had no effect on the amino acid sequence F(Phe)-F(Phe).

Genetic association of NALP1 with generalized vitiligo in Jordanian Arabs.

Generalized vitiligo is an autoimmune disorder characterized by patchy loss of pigmentation due to autoimmune destruction of melanocytes in the involved areas. Vitiligo is a polygenic, multifactorial disorder involving multiple genes and unknown environmental triggers. Recently, genetic variation in NALP1 (also called NLRP1), encoding a key regulator of the innate immune response, has been associated with generalized vitiligo in Caucasians of northern European origin. Here, we have investigated whether NALP1 is also associated with generalized vitiligo in Jordanian Arab patients. We genotyped 8 NALP1 single-nucleotide polymorphisms (SNPs) in 26 generalized vitiligo patients and 61 matched controls unaffected by vitiligo or any other autoimmune disorder. We found that two SNPs in the NALP1 extended promoter region, rs1008588 and rs2670660 were significantly associated with generalized vitiligo in our cohort of Arab vitiligo patients, and several other SNPs in the NALP1 region were at the margin of significant association. These results indicate that NALP1 is associated with susceptibility to generalized vitiligo in Arabs, as in Caucasians. Whether the casual variants are the same of not is yet to be identified by functional analysis.

Clinical characteristics and PTPN22 1858C/T variant analysis in Jordanian Arab vitiligo patients.

BACKGROUND AND OBJECTIVE: Vitiligo is an autoimmune polygenic disorder, characterized by loss of pigmentation due to melanocyte destruction. Multiple genes and environmental triggers are thought to play a role in inducing vitiligo. These genes and environmental factors differ across different populations. In this study, we investigated vitiligo patients in Jordan for patient characteristics and analyzed the association of the 1858C/T (rs2476601, R620W) variant of the PTPN22 gene with vitiligo in our patients. METHODS: Fifty-five patients with generalized vitiligo and 85 matched normal control subjects who did not have vitiligo or any apparent autoimmune disorder were recruited and interviewed for clinical and demographic characteristics. DNA samples were obtained from patients and controls and genotyped by restriction fragment length polymorphism for the 1858C/T variant. Fifty-three percent of our patients (29 of 55 overall) were female, the average age at onset was 19.2 years, 84.3% of patients (43 of 51 reported) had changing size of depigmented patches, 3.8% (2 of 53 reported) had other autoimmune disease, and 19.2% (5 of 26 reported) had a family history of vitiligo. RESULTS: The allelic frequency of 1858T (620W) was 1.9% in patients as opposed to 2.9% in controls (p = 0.5). No PTPN22 1858 TT homozygotes were observed among patients or controls; 3.8% of vitiligo patients were 1858 CT heterozygotes compared with 5.9% of controls (p = 0.7). Consequently, no significant association was observed between the 1858C/T functional variant and vitiligo patients. CONCLUSION: Although the PTPN22 1858C/T variant has been reported to play a role in increasing the risk of vitiligo in Caucasian patients, it does not appear to play a similar role in the Jordanian population, though a larger cohort of patients might be needed to confirm such a conclusion.

FGFR3 mutational status and protein expression in patients with bladder cancer in a Jordanian population.

Bladder cancer accounts for nearly 5% of all newly diagnosed cancers in Jordan, with a much higher frequency in males. Recent studies have shown that activating mutations in FGFR3 are the most common findings in non-invasive low grade bladder tumors. In this study, we, retrospectively, investigated a cohort of 121 bladder cancer patients with various grades and stages of the tumor for molecular changes in FGFR3. Overexpression of FGFR3 was observed in 49%, 34%, 15%, and 2% of pTa, pT1, pT2, and pT3 cases, respectively. Further, FGFR3 expression was positive in 45%, 26%, and 30% of G1, G2 and G3 cases, respectively. Mutational analysis of exons 7, 10 and 15 of FGFR3 identified four previously reported mutations, namely R248C (n=4; 10%), S249C (n=23; 59%), Y375C (n=7; 18%), G382R (n=4; 10%), and one novel mutation, G382E (n=1; 3%). Our results indicate that both mutations and overexpression of FGFR3 are correlated together, and are more prevalent in early stage (pTa and pT1) and low grade (G1 and G2) bladder tumors. Survival analysis showed no contribution of changes in FGFR3 on the patient's survival. Multivariate Cox proportional hazards model analysis of overall survival for the following variables: age, gender, stage and grade of tumor, and FGFR3 (expression and mutation) revealed that age, stage and grade of tumor are independent predictors of overall survival in patients with bladder cancer. Our work is the first to address the molecular status of FGFR3 in Jordanian patients with bladder cancer, and provides further support for FGFR3 as a key player in the initiation of bladder tumors.