Abstract. autosomal recessive non-syndromic hearing impairment (arnSHi) is caused by mutations in the gap junction gene GJB2 (connexin 26; cx26) in numerous human populations. The aim of this study was to determine the frequency of six GJB2 mutations in 50 Syrian families with congenital deafness and in 180 controls. Pcr-rFlP was used to detect the 35delG, 167delT, M34T, W24X, W77r and e47X mutations, and direct sequencing was performed for the 35delG mutation. The data revealed a high prevalence of the 35delG mutation among deaf families. Homozygous 35delG was detected in fifteen of the Syrian families (30%). a compound heterozygous genotype was observed in two families: one with the 35delG/167delT mutation (2%) and one with the 35delG/M34T mutation (2%). Nine families were heterozygous with no second identified mutation in Cx26: four with 35delG+/unknown (8%), four with 167delT/unknown (8%) and one with M34T/unknown (2%). The W24X, W77R and e47X mutations were not detected in any of the study subjects. Three individuals with the heterozygous 35delG genotype (1.66%) and five with the heterozygous 167delT genotype (2.77%) were detected among the controls. No other mutations were found among the controls. These results have important implications for the diagnosis and counseling of families with cx26 deafness.

Background: Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche or premature depletion of ovarian follicles. Bone morphogenetic protein 15 (BMP15) is an oocyte-derived growth factor acting as a major player in follicle differentiation in mammals. Mutations in this gene, lead to defective secretion of bioactive dimmers. The present study was to verify the involvement of BMP15 variations in POF women in Syria.Results: Genetic screening of 65 patients with POF, 55 primary amenorrhea (PA), 10 secondary amenorrhea (SA) and 100 controls of Syrian origin was done. Five variants in six patients were observed, including two missense substitutions: p. N103S

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Objective: Activating mutations of the fms-like tyrosine kinase 3 gene ( FLT3 ) by internal tandem duplications (ITDs) in the juxtamembrane domain (JMD) have been reported in ~30% of adult acute myeloid leukemia (AML) patients with cytogenetically normal karyotype (CN). However, FLT3 /ITD mutations are frequently accompanied with leukocytosis, high percentage of blasts in bone marrow (BM), and increased the risk of treatment failure in AML patients. FLT3 -ITD mutated AML patients mainly with normal karyotype have higher relapse probability and shorter duration of complete remission (CR) after chemotherapy, so FLT3 -ITD mutation is considered as an independent poor prognostic factor in AML. Methods: FLT3 -ITD and FLT3 -KTD were studied by polymerase chain reaction (PCR) and restriction fragment length polymorphism- PCR (RFLP-PCR) in 44 adults AML patients with cytogenetically normal karyotype (AML-CN) at diagnosis to characterize FLT3 status. The results were correlated with the prognostic factors. Results: In this study, FLT3 -ITD mutations were identified in 7 (15.9%) of the 44 AML-CN patients. Among the 7 patients with FLT3 /ITD mutations, 6 patients revealed a typical ITDs mutation (fragment size was 329 bp) and one patient showed untypical ITD mutation (fragment size was ~400 bp). Whereas 37 patients (61.7%) were FLT3 -ITD. None of all AML-CN patients examined showed FLT3 -KTD mutations. Conclusions: Our results support that FLT3 -ITD are independent adverse prognostic factors for elderly AML-CN patients and are associated with low overall survival (OS), low rate of CR, high relapse rate (RR), and high percentage of BM blast at diagnosis. We concluded, FLT3 mutation analysis should be performed as a routine test in AML-CN patients.

Nucleophosphomin (NPM1) is a nucleocytoplasmic shuttling protein that plays an active role in ribosomal protein assembly, chromatin remodeling, DNA repair, replication, and transcription (Lindstrom 2011). Mutations in the NPM1 gene have been reported in 25-35% of

Background Approximately 30% of adult acute myeloid leukemia (AML) acquire within fms-like tyrosine kinase 3 gene (FLT3) internal tandem duplications (FLT3/ITDs) in their juxtamembrane domain (JMD). FLT3/ITDs range in size from three to hundreds of nucleotides, and confer an adverse prognosis. Studies on a possible relationship between of FLT3/ITDs length and clinical outcomes in those AML patients were inconclusive, yet. Case presentation Here we report a 54-year-old Arab male diagnosed with AML who had two FLT3-ITD mutations in addition to NPM1 mutation. Cytogenetic approaches (banding cytogenetics) and fluorescence in situ hybridization (FISH) using specific probes to detect translocations t(8;21), t(15;17), t(16;16), t(12;21), and deletion del(13q)) were applied to exclude chromosomal abnormalities. Molecular genetic approaches (polymerase chain reaction (PCR) and the Sanger sequencing) identified a yet unreported combination of two new mutations in FLT3-ITDs. The first mutation induced a frameshift in JMD, and the second led to a homozygous substitution of c.1836T>A (p.F612L) also in JMD. Additionally a NPM1 type A mutation was detected. The first chemotherapeutic treatment was successful, but 1 month after the initial diagnosis, the patient experienced a relapse and unfortunately died. Conclusions To the best of our knowledge, a combination of two FLT3-ITD mutations in JMD together with an NPM1 type A mutation were not previously reported in adult AML. Further studies are necessary to prove or rule out whether the size of these FLT3-ITDs mutations and potential other double mutations in FLT3-ITD are correlated with the observed adverse outcome.

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