Mutations of BRCA1/2 Genes in the West of Turkey and Genotype-Phenotype Correlations.

BACKGROUND: Mutations of the BRCA1/2 genes are associated with increased breast and ovarian cancer. The aim of this study was to investigate the founder mutations of the BRCA1 and BRCA2 genes in the Turkish population in the Aegean region as well as their genotype-phenotype correlations. METHODS: All the patients were provided with BRCA1/2 testing criteria according to the National Comprehensive Cancer Network. QIAseq Targeted DNA Panels were used for the BRCA1/2 coding regions. RESULTS: Of the 181 studied patients, 38 (21%) were found to carry pathogenic or likely pathogenic mutations, while 20 (11%) patients were found to carry variants of unknown significance. The most common pathogenic mutations were NM_000059.4:c.2765dup in the BRCA2 gene and NM_007300.4:c.981_982del and NM_007294.3:c. 5266dup in the BRCA1 gene. p.Lys3326* was the most frequently detected variant of unknown significance (6/ 181). Regarding genotype-phenotype correlations, the NM_007300.4:c.981_982del mutation in BRCA1 gene was found to be milder in terms of breast cancer. The most frequent cancers other than those related to BRCA genes, observed in the relatives of the patients who had pathogenic variants and variants of unknown significance, were endometrium cancer and leukemia, respectively. CONCLUSIONS: NM_007294.3:c.5266dup was found to be a candidate founder mutation in the Turkish population. NM_007300.4:c.981_982del mutation seems to have a milder course in terms of breast cancer. A significantly increased frequency of p.Lys3326* variant in breast cancer and ovarian cancer patients compared with that in the 1,000 Genomes Project suggesting that this variant has a slight effect on BRCA2 function.

Genes predisposing tunneled catheter thrombosis in hemodialysis patients.

Background: This study aims to investigate the association of genes predisposing thrombophilia with tunneled catheter thrombosis in hemodialysis patients. Methods: Between October 2018 and December 2020, we compared the frequencies of genetic polymorphisms causing thrombophilia, including prothrombin G20210A, factor V Leiden, methylene tetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, plasminogen activator inhibitor (PAI), factor XIII V34L and clinical characteristics of 52 patients with a history of 2 tunneled2 tunneled catheter thrombosis occlusions within a year (Group 1; 24 males, 28 females; mean age: 62±8.9 years; range, 45 to 77 years), 52 patients who underwent their first tunneled catheter thrombosis insertion (Group 2; 29 males, 23 females; mean age: 63±15.2 years; range, 22 to 87 years), and 51 healthy controls (Group 3; 26 males, 25 females; mean age: 34±9.2 years; range, 19 to 54 years). Results: Groups 1 and 2 carried the MTHFR A1298C (p=0.048) and compound heterozygous MTHFR A1298C and C677T (p=0.048) polymorphisms more frequently than Group 3. However, subgroup analysis results were not statistically significant. The other polymorphisms were distributed similarly in all three groups. The MTHFR polymorphisms had a weak effect on tunneled hemodialysis catheter thrombosis in neural network analysis. Conclusion: Our study results indicated that there was a concomitance of MTHFR polymorphisms with hemodialysis-dependent chronic kidney disease. The MTHFR A1298C and compound heterozygous MTHFR polymorphisms may be associated with tunneled hemodialysis catheter thrombosis. Thrombophilia gene screening may be recommended in hemodialysis patients undergoing tunneled hemodialysis catheter thrombosis at least twice in a year.

Coinheritance of novel mutations in NAGLU causing mucopolysaccharidosis type IIIB and in DDHD2 causing spastic paraplegia54 in a Turkish family.

Mucopolysaccharidosis type IIIB (MPSIIIB) is one of the lysosomal storage diseases, clinically related to developmental delay in the early phase and loss of skills in the late phases of the disease. The disease is caused by homozygous mutations in the NAGLU gene. Spastic paraplegia54 (SPG54) is a neurodegenerative disorder caused by homozygous mutations in the DDHD2 gene. Clinical features are progressive spasticity and weakness in the lower limbs and corpus callosum agenesis. We report on two siblings in a consanguineous family, presenting both the clinical and molecular diagnoses of MPSIIIB and SPG54 with novel mutations by using whole exome sequencing (WES). This interesting finding shows that we should be aware of the importance of using WES for diagnosing rare diseases in consanguineous families.

A new clinical entity in T704M mutation in periodic paralysis.

Periodic paralyses (PPs) are a group of rare disorders characterized by episodic, sudden-onset, flaccid paralysis of skeletal muscles usually resulting in complete recovery after the attacks. PPs are caused by abnormal, mostly potassium-sensitive excitability of the muscle tissue. Hypokalemic and hyperkalemic periodic paralysis (HypoKPP and HyperKPP) have been described according to their characteristic phenotypes and the serum potassium level during the attacks of weakness. The T704M mutation on the SCN4A gene is the most common mutation in HyperKPP. Different mutations of the SCN4A gene have also been reported in some cases of HypoKPP. In this study, a large Turkish family carrying the T704M mutation on the SCN4A gene with HypoKPP disease was examined. A similar history was noted in a total of 17 subjects in the pedigree. SCN4A gene of the patients was sequenced with Sanger sequencing. In this study, this mutation was associated with a HypoKKP diagnosis for the first time in the literature. The symptoms of hallucination and diplopia seen in patients had also never been indicated in the literature before. This report expands the phenotypic variability of the T704M mutation, further confirming the lack of genotype-phenotype correlation in SCN4A mutations.