Identification of novel MYH14 variants in families with autosomal dominant sensorineural hearing loss.

Autosomal dominant sensorineural hearing loss (ADSNHL) is a genetically heterogeneous disorder caused by pathogenic variants in various genes, including MYH14. However, the interpretation of pathogenicity for MYH14 variants remains a challenge due to incomplete penetrance and the lack of functional studies and large families. In this study, we performed exome sequencing in six unrelated families with ADSNHL and identified five MYH14 variants, including three novel variants. Two of the novel variants, c.571G > C (p.Asp191His) and c.571G > A (p.Asp191Asn), were classified as likely pathogenic using ACMG and Hearing Loss Expert panel guidelines. In silico modeling demonstrated that these variants, along with p.Gly1794Arg, can alter protein stability and interactions among neighboring molecules. Our findings suggest that MYH14 causative variants may be more contributory and emphasize the importance of considering this gene in patients with nonsyndromic mainly post-lingual severe form of hearing loss. However, further functional studies are needed to confirm the pathogenicity of these variants.

Genome sequencing identifies coding and non-coding variants for non-syndromic hearing loss.

Hearing loss (HL) is a common heterogeneous trait that involves variants in more than 200 genes. In this study, we utilized exome (ES) and genome sequencing (GS) to effectively identify the genetic cause of presumably non-syndromic HL in 322 families from South and West Asia and Latin America. Biallelic GJB2 variants were identified in 58 probands at the time of enrollment these probands were excluded. In addition, upon review of phenotypic findings, 38/322 probands were excluded based on syndromic findings at the time of ascertainment and no further evaluation was performed on those samples. We performed ES as a primary diagnostic tool on one or two affected individuals from 212/226 families. Via ES we detected a total of 78 variants in 30 genes and showed their co-segregation with HL in 71 affected families. Most of the variants were frameshift or missense and affected individuals were either homozygous or compound heterozygous in their respective families. We employed GS as a primary test on a subset of 14 families and a secondary tool on 22 families which were unsolved by ES. Although the cumulative detection rate of causal variants by ES and GS is 40% (89/226), GS alone has led to a molecular diagnosis in 7 of 14 families as the primary tool and 5 of 22 families as the secondary test. GS successfully identified variants present in deep intronic or complex regions not detectable by ES.

Contribution of genotypes in Prothrombin and Factor V Leiden to COVID-19 and disease severity in patients at high risk for hereditary thrombophilia.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Analysis of ACE2 and TMPRSS2 coding variants as a risk factor for SARS-CoV-2 from 946 whole-exome sequencing data in the Turkish population.

Heterogeneity in symptoms associated with COVID-19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID-19. In this study, a retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole-exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS-CoV-2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS-CoV-2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS-CoV-2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS-CoV-2 infection among other populations.

A comprehensive molecular analysis and genotype-phenotype correlation in patients with familial mediterranean fever.

Familial Mediterranean fever is an auto inflammatory genetic disease involving especially Turks, Armenians, Arabs and non-Ashkenazi Jews and caused by variants in the MEFV gene. In this study, we aimed to evaluate the distribution and frequency of clinical, MEFV gene variants in FMF patients and the relationship between mutations in different exons and phenotype-genotype and clinical findings. 1028 patients diagnosed as FMF were included. The most common genotypes were M694V / R202Q heterozygous (10.4%), M694V homozygous (7.5%), M694V / E148Q / R202Q heterozygous (4.6%), V726A heterozygous (4.5%), M680I heterozygous (4.2%). c.1611-1 G > C, G152R, S104C, R116S, E336K, R461Q mutations were detected in the literature for the first time in FMF patients. We also divided the patients into 4 groups according to whether the MEFV mutations were exon 10 or non-exon 10. The first group consisted of non-exon 10 homozygous or compound heterozygous (n = 180) patients, Group 2 consisted of exon 10- non-exon 10 compound heterozygous (n = 318) patients, Group 3 consisted of exon 10 homozygous or compound heterozygous (n = 256) patients, while Group 4 consisted of heterozygous (n = 227) patients at any exon. There was no significant difference between the groups in terms of abdominal pain, arthritis, arthralgia, vomiting diarrhea, erysipelas like rash, amyloidosis, renal failure family history. There was no difference in fever between Group 1 (55.6%) and 2 (62.3%); however, these two groups were different from Group 3 (75.8%) and 4 (76.7%). Group 3 (18.8%) had the highest rate of appendectomy. In addition, allele frequencies of all mutations detected in the analyses were compared with allele frequencies of healthy people in the gnomad database. It is useful to analyse all exons in the MEFV gene with the next generation sequence analysis in the detection of FMF disease. S104C, R116S, G152R, E336K, R461Q, L508Q and c.1611-1 G > C mutations are also new variants in literature. c.1611-1 G > C is a possible pathogenic variant.

Increased vitamin D receptor gene expression and rs11568820 and rs4516035 promoter polymorphisms in autistic disorder.

Although there are a large number of sequence variants of different genes and copy number variations at various loci identified in autistic disorder (AD) patients, the pathogenesis of AD has not been elucidated completely. Recently, in AD patients, a large number of expression array and transcriptome studies have shown an increase in the expression of genes especially related to innate immune response. Antimicrobial effects of vitamin D and VDR are exerted through Toll-Like-Receptors (TLR) which have an important role in the innate immune response, are expressed by antigen presenting cells and recognize foreign microorganisms. In this study, age and gender matched 30 patients diagnosed with AD and 30 healthy controls were included in the study. Comparatively whole blood VDR gene expression and rs11568820 and rs4516035 SNP profile of the promoter region of the VDR gene were investigated by real time PCR. Whole blood VDR gene expression was significantly higher in the AD group compared to control subjects (p < 0.0001). There were no significant differences among allele and genotype distribution of rs11568820 and rs4516035 polymorphisms between AD patients and controls. The increase of VDR gene expression in patients with AD may be in accordance with an increase in the innate immune response in patients with AD. Furthermore, this study will stimulate new studies in order to clarify the relationship among AD, vitamin D, VDR, and innate immunity.

Does thiol-disulphide balance show oxidative stress in different MEFV mutations?

Many studies have shown that oxidative stress levels increase in patients with Familial Mediterranean Fever (FMF). Thiols are a class of compounds that include a sulfhydryl group (-SH) and can react with free oxygen radicals to protect tissues. We aimed to investigate thiol-disulphide homeostatic status in FMF patients and examined the effect of different mutations in the MEFV gene on the thiol-disulphide balance. We investigated thiol-disulphide parameters in patients with FMF and healthy controls. To determine the differential effect of MEFV gene mutations on thiol-disulphide balance, subjects were divided into five groups based on homozygous or compound heterozygous exon 10 and nonexon 10 mutations. Tests of thiol-disulphide homeostasis were conducted using the automated spectrophotometric method. Patients with FMF had significantly lower native thiol [433.8 µmol/l (243.3-536.4) vs. 484.1 µmol/L (340.2-612.3), p  < 0.001], total thiol levels [459.7 µmol/L (281.3-575.4) vs. 529.9 µmol/L (363-669.5), p < 0.001], and disulphide levels [14.0 µmol/l (2.7-33.3) vs. 24.4 µmol/l (7.2-36.6), p < 0.001] compared to the control group. Moreover, disulphide/native thiol (3.4 ± 1.7 vs. 4.7 ± 1.3, p < 0.001) and disulphide/total thiol (3.1 ± 1.4 vs. 4.3 ± 1.0 p < 0.001) were also detected lower in the FMF group compared to the control group. But the native thiol/total thiol ratios (93.6 ± 2.9 vs. 91.3 ± 2.1, p < 0.001) were higher in the FMF group. There was no significant difference between the native thiol, total thiol, and disulphide levels of individuals with nonexon 10 homozygous or compound heterozygous (Group 1), nonexon 10-exon 10 compound heterozygous (Group 2), exon 10 homozygous or compound heterozygous (Group 3), and heterozygous (Group 4) mutations. However, these parameters significantly differed from those of the healthy control group. Since no differences were found in our study between thiol and disulfide levels of Groups 1, 2 and 3, we believe that this rate cannot be shown as an indicator of oxidative damage in different mutations of FMFs. To the best of our knowledge, this study is the first study that demonstrates the effect of different FMF mutations on the thiol-disulphide balance.

Interstitial deletion 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with clubfoot, blepharophimosis, arthrogryposis, and multiple congenital abnormalities.

Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high-pitched cat-like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.

The Association of Brain-Derived Neurotrophic Factor Gene Polymorphism with Obstructive Sleep Apnea Syndrome and Obesity.

BACKGROUND: Obesity represents a major risk factor for Obstructive Sleep Apnea Syndrome (OSAS). Brain-derived neurotrophic factor (BDNF) affects the mechanisms that regulate weight, eating behavior, and metabolism. This project aims to investigate the possible association of BDNF gene polymorphism with obesity and OSAS, and to contribute knowledge to the understanding of the pathophysiology of OSAS. METHODS: The subjects included in this study were selected among the individuals who were hospitalized in the Erciyes University Medical School Chest Diseases Sleep Medicine Laboratory. Subjects were divided into four groups based on the presence of OSAS and/or obesity. Group 1 included OSAS+ obesity+ patients, Group 2 included OSAS+ obesity- patients, Group 3 included OSAS- obesity+ patients, and Group 4 included OSAS- obesity- patients. The targeted patient number per each study group was 45, but only 32 patients could be enrolled into Group 3. RESULTS: Out of a total number of 167 subjects, 117 (70.1 %) had BDNF 196G/G, 48 (28.7 %) had BDNF 196G/A, and 2 (1.2 %) had BDNF 196A/A genotype. Of 48 subjects having BDNF 196G/A genotype, 32 (66.6 %) were obese, and 16 (33.3 %) were non-obese. Out of 90 subjects with OSAS, 64 (71.1 %) had BDNF 196G/G, and 25 (27.8 %) had BDNF 196G/A genotype. Out of 77 subjects without OSAS, BDNF 196G/G, and BDNF 196G/A genotypes were detected in 53 (68.8 %) and 23 (29.9 %) subjects, respectively. A statistically significant difference was demonstrated between the four study groups in terms of BDNF rs6265 polymorphism (p = 0.013). This difference was attributed to OSAS+ obesity- Group, in which BDNF 196G/G genotype was more common and BDNF 196G/A polymorphism was less common than the patients in other groups. CONCLUSION: In conclusion, BDNF 196G/A genotype was found to be more frequent among obese patients compared to the non-obese individuals, but it was not significantly related to OSAS in the present study. BDNF196G/G genotype was more common and BDNF 196G/A polymorphism was less common among OSAS+ obesity- subjects compared to the other study groups.

Is there relation between COL4A1/A2 mutations and antenatally detected fetal intraventricular hemorrhage?

BACKGROUND: The aim of the present study is to evaluate the role of COL4A1/A2 mutations in the etiology of intraventricular hemorrhage (IVH) detected in-utero. METHODS: The data of four cases with fetal IVH were analyzed retrospectively. Antenatal risk factors, clinical features, postnatal outcome, and the presence of COL4A1/A2 mutations were evaluated. RESULTS: Eight cases of fetal IVH were diagnosed between 2005 and 2012 in Erciyes University. Of these, four were eligible for genetic analysis. Mean gestational age at diagnosis was 30 weeks 5 day (min-max: 28-34 weeks); two cases had grade III hemorrhage and two cases had grade IV hemorrhage according to fetal magnetic resonance imaging. Three cases had severe neurodevelopmental delay and one case had mild deficit. In all cases, postnatal evaluation revealed no underlying cause, and no retinal hemorrhagia and hematuria were detected. The mean postnatal follow-up was 19 months, and no recurrent hemorrhages and porencephalic cyst formation were observed. The whole exome sequencing showed no pathological mutations of COL4A1 and COL4A2 in the four patients. CONCLUSION: Our data showed that fetal intraventricular hemorrhage is not associated with COL4A1 and COL4A2 mutations in the absence of porencephaly, recurrent hemorrhage, and other organ bleeding.

A c.1244G>A (p.Arg415Gln) mutation in SH3BP2 gene causes cherubism in a Turkish family: report of a family with review of the literature.

OBJECTIVES: The present study was aimed at advancing the understanding of the pathogenesis of cherubism by presenting a case study based on history, physical examination, typical radiological features, molecular and histopathological laboratory tests and a review of the literature. STUDY DESIGN: This study began with a 7-year-old boy who was referred due to mandibular overgrowth. A panoramic radiograph revealed multilocular radiolucent lesions of the upper/lower jaws suggestive of cherubism. Overall, a total of four family members were tested for SH3BP2 mutations, namely two siblings and their parents. Both siblings had been clinically diagnosed with cherubism; however, the parents were clinically normal. Peripheral blood was collected from all participants and genomic DNA sequencing was carried out. RESULTS: A missense mutation was found in the two affected siblings and their asymptomatic mother. The mutation was a 1244 G>A transversion which resulted in an amino acid substitution from arginine to glutamine (p.Arg415Gln) in exon 9. CONCLUSIONS: The present study emphasized the importance of further clinical and molecular investigation even when only a single case of cherubism is identified within a family. Genotype-phenotype association studies in individuals with cherubism are necessary to provide important insights into the molecular mechanisms associated with this disease.

A Novel Variant in AKAP9 Gene, a Controversial Gene, in Long QT Syndrome.

Introduction: Long QT syndrome (LQTS) is a common congenital cause of fatal cardiac arrhythmia. Characteristic clinical findings are prolonged QT interval and ventricular arrhythmia on electrocardiogram (ECG), syncope, seizure, and sudden death. It is a genetically heterogeneous disease. To date, disease-causing variant have been reported in seventeen genes. The AKAP9 is still considered controversial among those genes. Case Report: We report the case of a 10-year-old female who was born from a non-consanguineous Turkish couple. She visited pediatrics cardiology clinic presenting with dyspnea and tachycardia. Prolongation of the QT interval was detected in her ECG. Panel test associated with LQTS genes was performed. She was diagnosed with long QTS type 11 due to a heterozygous variant in AKAP9:c.11487_11489 delTACinsCGTA, p.(Thr3830ValfsTer12), that was revealed through next-generation sequencing test. The variant was also found in her mother and brother. Discussion and Conclusion: Novel heterozygous frameshift variant in the AKAP9 gene was considered as "Uncertain Significance (VUS)" in the ACMG classification. The novel variant is absent from population databases (PM2); it is a null variant (PVS1_moderate). AKAP9 gene has the lowest known rate among the causes of LQTS. Information is limited on genotype-phenotype correlation. Yet it is still among the candidate genes. Although the relationship of the AKAP9 gene with LQTS has not yet been fully indicated, individuals with a pathogenic variant in AKAP9 gene and silent carriers may be at risk for fatal cardiac events. Improvements of the genetic tests in the near future may contribute to the literature and clinical research about AKAP9 gene.

A case of dichorionic twin pregnancy concordant for bilateral cleft lip and palate and discordant for spina bifida; schisis association.

BACKGROUND: The schisis theory suggests that neural tube defect (NTD), cleft lip and palate (CL/P), omphalocele and diaphragmatic hernia are associated to each other more frequently than at the expected random combination rates in a given fetus. However, it is unusual to see schisis-associated defects concordantly in dichorionic twin pregnancy with other schisis-associated and non-associated defects. In addition, the association of lower limb oligodactly with oral cleft and spina bifida has not been reported before. CASE: A 24-year-old woman with twin gestation at 21 weeks was referred to our unit. At ultrasound examination, bilateral CL/P and single umbilical artery in male fetus, and bilateral CL/P and open lumbar spina bifida in female fetus were revealed. At autopsy, oligodactyly of both lower limbs was demonstrated in the female fetus. The parents had no family history of NTD and CL/P. There was no consanguinity, nor was the mother exposed to teratogens.

The role of TNF-α and PAI-1 gene polymorphisms in familial Mediterranean fever.

OBJECTIVES: Familial Mediterranean fever (FMF) is one of the most serious inherited inflammatory disorders among Jewish, Armenian, Turkish and Arab populations. The imbalance between pro- and anti-inflammatory cytokines may play a role in its etiology. We have investigated whether tumor necrosis factor-alpha (TNF-α) and plasminogen activator inhibitor 1 (PAI-1) gene polymorphisms are associated with FMF and evaluated the relationship between these polymorphisms and genotypic manifestation of FMF. METHODS: We investigated single nucleotide polymorphisms of the TNF-α promoter at positions -308 G/A and the PAI-1 4G/5G gene polymorphism in peripheral blood leukocytes collected from 177 individuals with FMF with different genotype combinations. All of the polymorphisms of TNF-α and PAI-1 were detected by PCR and restriction fragment length polymorphism analysis. RESULTS: There were no association between the TNF-α/308 genotypes and mutations in FMF. In contrast, the PAI-1 4G/5G gene polymorphism may have a significant effect in FMF disease. CONCLUSIONS: Screening with PAI-1 gene polymorphism tests may be beneficial for tracing future FMF patients. However, further investigations are needed to reach a conclusion on the association between PAI-1 polymorphisms and FMF.

The Genetic Analysis of Cystic Fibrosis Patients With Seven Novel Mutations in the CFTR Gene in the Central Anatolian Region of Turkey.

BACKGROUND: Cystic fibrosis, a pulmonary disease which is an autosomal recessive, inherited, multisystemic genetic disease commonly seen in the Caucasian race, is the most frequent cause of mortality and morbidity. So far, more than 2000 disease-causing gene variants have been found and this number has been increasing with the studies conducted. Although there is not yet enough data that include the Turkish population, the recent increase of studies is noteworthy. AIMS: To discover the genetic variation in patients diagnosed with cystic fibrosis in the Central Anatolian region. STUDY DESIGN: Cross-sectional study. METHODS: The study was carried out in the Central Anatolian region in 3 pediatric pulmonology departments (Kayseri, Konya, and Ankara) in Turkey between July 2014 and December 2017. The Sanger and Next Generation Sequence analyses were used for exon and exon-intron boundaries in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene, and in selected patients, mutation analysis was performed using the Multiplex Ligation-dependent Probe Amplification technique for large deletions and duplications. RESULTS: CFTR gene analysis was performed for 316 patients and 215 of them were genetically diagnosed with cystic fibrosis. Sixtythree different variants were defined in these patients and 7 of these were large deletions/duplications detected with the MLPA method. The most frequent variants were F508del (29.6%), G85E (8.2%), N1303K (8.2%), Y515* (7.5%), and G542* (3.4%). CONCLUSION: Using sequencing and Multiplex Ligation-dependent Probe Amplification methods, the identification of seven new mutations that were not previously reported in the literature contributes to a better understanding of the heterogeneous nature of CFTR mutations in the Turkish population. When no mutations are detected (pathogenic/probably pathogenic) in clinically compatible cases, Multiplex Ligationdependent Probe Amplification analysis contributes significantly to the diagnosis.

Frequent Mutation in the FTL Gene Causing Hyperferritinemia Cataract Syndrome in Turkish Population Is c.-160A>G

Objective: Hyperferritinemia cataract syndrome (HFCS) is an autosomal dominantly inherited disease characterized by increased serum ferritin levels and bilateral cataract formation in the early period of life. Heterozygote mutations in the 5' untranslated region of the L-ferritin gene (FTL) have been reported to cause this disease. In this study, our purpose was to research the FTL gene mutations that cause HFCS in Central Anatolia and the clinical effects of these mutations. Materials and Methods: Seventeen patients from 6 families with high ferritin levels in performed serum measurements, those who were found to have cataracts in eye examinations, and families with vertical inheritance, since the disease is autosomal dominant, were included in the study. Exons, exon-intron boundaries, and 5' and 3' untranslated regions of FTL (NM_000146) were sequenced using the Sanger sequencing method. Results: The female/male ratio of the patients was 7/10. All of the patients were found to have c.-160A>G heterozygous mutation in the FTL gene. Conclusion: In the Turkish population, the prevalence of HFCS is about 1/100,000 and the commonly observed mutation is c.-160A>G mutation.

Decreased disulphide/thiol ratio in patients with autosomal recessive non-syndromic hearing loss.

INTRODUCTION: Oxidative stress plays a key role in the formation of age-related, noise-induced and drug-induced hearing loss. Thiols are organic compounds which can react with free radicals to protect against tissue and cell damage caused by reactive oxygen. There are no studies in literature on the association between autosomal recessive non-syndromic hearing loss(ARNSHL) including GJB2 and non-GJB2 mutations and thiol-disulphide balance. In this study, we aim to assess whether thiol-disulphide balance is disrupted in patients with ARNSHL. METHODS: Thirty-one ARNSHL patients and thirty-one healthy controls were included in this study. Patients whose parents were first degree cousins and who had at least two congenital hearing loss in the same family were included in the study. Audiological tests included air - bone pure tone audiometry and auditory brain stem response. GJB2 gene analysis was performed using sanger sequence method. Tests of thiol/disulphide homeostasis were conducted using the automated spectrophotometric method. We first investigated whether there was a significant difference between ARNSHL patients and healthy controls. Then, in order to determine the differential effect of the GJB2 gene mutations and non-GJB2 gene mutations on the thiol-disulphide balance, subjects were divided into three groups: Group 1 included patients with GJB2 mutations; Group 2 included patients with non-GJB2 mutations; Group 3 included healthy subjects. RESULTS: Patients with ARNSHL had significantly higher native thiol (411.6 ±â€¯54.3 µmol/l vs. 368.0 ±â€¯64.3 µmol/l, p = 0.006), total thiol levels (440.3 ±â€¯56.2 µmol/l vs. 402.4 ±â€¯65.9 µmol/l, p = 0.018), and lower disulphide levels (14.3 ±â€¯5.7 µmol/l) vs. (17.1 ±â€¯4.9 µmol/l), (p = 0.043) compared to the control group. Moreover, disulphide /native thiol (p < 0.001) and disulphide/total thiol (p < 0.001) were also detected lower in the ARNSHL group compared to the control group. Thiol-disulphide hemostasis parameters between all three groups showed that the native thiol and total thiol were increased in the Group 1 and Group 2. The disulphide levels decreased in Group 1 and 2, although not statistically significant. CONCLUSION: It was shown that thiol levels increased and disulphide levels decreased in patients with autosomal recessive non-syndromic hearing loss. It also may suggest that there is a reverse association between ARNSHL and oxidative stress. Further studies are needed on whether or not ARNSHL cause oxidative stress limited to the inner ear and cochlea.

A novel PTCH1 gene mutation in a pediatric patient associated multiple keratocystic odontogenic tumors of the jaws and Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome (GGS) is an uncommon autosomal dominant inherited disorder which comprises the triad of basal cell carcinomas (BCCs), odontogenic keratocysts, and musculoskeletal malformations. Besides this triad, neurological, ophthalmic, endocrine, and genital manifestations are known to be variable. It is occasionally associated with aggressive BCC and internal malignancies. This report documents a case of GGS with a novel mutation in the PTCH1 gene in an 11-year-old child. The clinical, radiographic, histopathologic and molecular findings of this condition, and treatment are described, and a review of GGS was carried out.