A Case Series of Three Patients with Cleidocranial Dysplasia: Clinical Presentation and Diagnostic Considerations.

Cleidocranial dysplasia (CCD) is a rare genetic condition that affects the bones and teeth. In our study, we presented three cases of CCD, including one with a new mutation and two with a family history. Case 1 had a unique heterozygous frameshift mutation (NM_001015051,c.762del, p.(Ser256Valfs*2)), while Case 2 and her brother (Case 3) had a common pathogenic missense mutation (NM_001015051,c.674G, p.Arg225Gln), which was also found in their father. The mutation in Case 1 was not reported before. Interestingly, the symptoms in Case 1, with the new mutation, were less severe than the other cases and the previous reports.

Evaluation of chromosomal abnormalities in the postnatal cohort: A single-center study on 14,242 patients.

BACKGROUND AND AIM: Chromosomal analysis is a laboratory technique used to examine the chromosomes of an individual, offering insights into chromosome numbers, structures, and arrangements to diagnose and comprehend genetic diseases. This retrospective study provides a comprehensive understanding of the distribution by indications in a large cohort of 14,242 patients and the frequency of chromosomal abnormalities in different clinical populations. METHOD: The study examined various indications for karyotype evaluation, with recurrent pregnancy loss being the most common indication, followed by intellectual disability, dysmorphic features, congenital anomalies, and developmental delay. RESULTS: The overall chromosomal abnormality rate was found to be 5.4%, with numerical abnormalities accounting for the majority of cases (61.7%). Trisomies, particularly trisomy 21, were the most frequent numerical abnormalities. In terms of structural abnormalities, inversions and translocations were the most commonly identified. The rates of chromosomal anomalies varied in specific indications such as amenorrhea, disorders of sex development, and Turner syndrome. The study also highlighted significant differences between males and females in the presence of chromosomal abnormalities across certain indications. Males exhibited a higher incidence of chromosomal abnormalities in cases of Down syndrome and infertility, whereas females showed higher abnormalities in terms of recurrent pregnancy loss. CONCLUSION: While this study provides valuable insights into the frequency and distribution of chromosomal abnormalities, it has limitations, including its retrospective design and reliance on data from a single medical genetics department. Nevertheless, the findings emphasize the importance of karyotype analysis in diagnosing chromosomal disorders and providing appropriate management, while also pointing to potential gender-related variations in chromosomal abnormalities that warrant further investigation.

Osteopontin as an early predictor of atherosclerosis in attack-free Familial Mediterranean fever patients.

Familial Mediterranean fever (FMF) is an autoinflammatory disease that is associated with endothelial dysfunction and atherosclerosis. Osteopontin which is a multifunctional protein involved in the modulation of inflammatory processes may contribute to the development of atherosclerosis in FMF patients. Therefore, this cross-sectional study investigated the relationship of osteopontin with carotid intima media thickness (CIMT) and atherogenic indices in patients with FMF. Serum osteopontin levels, CIMT, Castelli risk index I and II, plasma atherogenic index (PAI), non - high-density lipoprotein cholesterol, and atherogenic coefficient (AC) in 64 attack-free FMF patients were compared with levels in 23 healthy control subjects. The serum osteopontin level, CIMT, Castelli risk index I, AC and PAI were significantly higher, and high-density lipoprotein cholesterol was significantly lower in FMF patients (P < .001, P < .001, P = .045, P = .016, P = .045, and P = .024; respectively). There were significant positive correlations between osteopontin and CIMT, PAI, AC, and Castelli risk index I (R = 0.580, R = 0.259, R = 0.233, R = 0.277; respectively) and there was significant negative correlation between osteopontin and high-density lipoprotein cholesterol (r= -0.309). Patients who had homozygote mutations had significantly higher osteopontin, PAI, Castelli risk index I and II level. The current study is the first to demonstrate significantly increased serum osteopontin levels in attack-free FMF patients compared with healthy controls. It was also associated with CIMT and many atherogenic indices. This finding provides a new experimental basis to understand the pathogenesis of inflammation-induced atherosclerosis in FMF patients. Furthermore, patients who had homozygote mutations had worse atherogenic indices than those with heterozygote mutations.

Are MUC5B and TERT mutations genetic risk factors for pulmonary fibrosis in individuals with severe COVID-19?

Introduction: The genetic risk factors for Coronavirus disease-2019 (COVID19)-associated pulmonary fibrosis (CAPF) are not clearly defined. Mutations in the genes encoding telomerase reverse transcriptase (TERT) and mucin 5B (MUC5B) are well-known genetic risk factors for pulmonary fibrosis. In this study, we aimed to show whether the most common proven mutations of pulmonary fibrosis affect the development of CAPF. Materials and Methods: Forty-eight patients who were matched for age, gender, COVID-19 disease severity, and respiratory support type and needed high flow nasal cannula, non-invasive mechanical ventilator, or invasive mechanical ventilator due to COVID-19 were followed up prospectively. Eighteen patients were excluded from the follow-up due to known structural lung disease, collagen tissue disease, and occupational exposure to fibrosis. The patients were called for follow-up three months after discharge, and CT was performed. Those with fibrosis (n= 15) in the third-month follow-up CT were included in the CAPF group, and those with complete resolution (n= 15) were included in the control group. Blood samples were taken for genetic analysis. Result: TERT gene study revealed that six (40%) of the fibrosis group was normal, while five were heterozygous (33.3%). MUC5B polymorphism was not detected in 10 (66.7%) of the fibrosis group. Conclusions: Individuals with TERT mutations may be at a higher risk for CAPF. Further studies are needed to clarify the genetic risk factors for CAPF.

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.

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 truncating variant in the THOC6 gene with new findings in a patient with Beaulieu-Boycott-Innes syndrome.

Beaulieu-Boycott-Innes syndrome (BBIS; MIM#613680) is a rare, autosomal recessive neurodevelopmental genetic disorder associated with pathogenic variants in the THOC6 gene (*615403). Intellectual disability, dysmorphic facial features, developmental delay, structural cardiac and genitourinary anomalies, and dental caries are suggestive findings of the syndrome. Exome sequencing (ES) may facilitate the diagnosis of this syndrome, whose clinical features can be nonspecific. Here we report a BBIS patient with a homozygous truncating variant (NM_024339.5:c.299G>A; p.Trp100Ter) in the THOC6 gene, diagnosed by ES analysis. The patient's variant is novel and some features such as clivus dysplasia, occult spina bifida, tapered fingers, and upturned fleshy earlobes have not been reported in the literature before. This new case report will expand the knowledge of BBIS and provide more information about the genetic variants and phenotypic spectrum. Also, new cases with THOC6 variants will define the core clinical features and common phenotypes of the BBIS over time.

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.

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.

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.

Netherton syndrome previously misdiagnosed as hyper IgE syndrome caused by a probable mutation in SPINK5 C.

Özyurt K, Atasoy M, Ertas R, Ulas Y, Akkus MR, Kiraz A, Hennies HC. Netherton syndrome previously misdiagnosed as hyper IgE syndrome caused by a probable mutation in SPINK5 C. Turk J Pediatr 2019; 61: 604-607. Netherton syndrome (NS, MIM256500) is an autosomal recessive disorder that includes ichthyosis linearis circumflexa and a predisposition to allergies, asthma, and eczema, with hypereosinophilia, trichorrhexis invaginata, and elevated serum IgE levels. The genetic bases of Netherton syndrome are mutations in the gene SPINK5, and the Lymphoepitheial Kazal type related inhibitor, a serine protease inhibitor, is encoded by SPINK. Here a case is presented which showed a probable splice site mutation in SPINK5, which was previously unknown in databases and the literature, to point out the misdiagnosis of Hyper IgE Syndrome in the early presentation of the phenotype. This case highlights that a genetic test can be critical for identifying NS. The finding of underlying mutations contributes to the understanding of Netherton syndrome and is instrumental in indicating a specific therapy. Notably, treatment with acitretin has significantly improved both the ichthyosis linearis circumflexa and eczema in our patient.

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 Rare Cause of Neonatal Hemolytic Anemia: Glutathione Synthetase Deficiency.

BACKGROUND: Isolated hemolysis or hemolytic anemia and 5-oxoprolinuria are 2 distinct medical conditions in the clinical spectrum associated with glutathione synthetase deficiency. CLINICAL OBSERVATION: A 1-day-old female baby presented with anemia and respiratory distress. Her hemoglobin level was 9.5 g/dL and the total serum bilirubin level was 5.6 mg/dL. Metabolic acidosis was detected in her blood gas analysis. Metabolic acidosis recurred despite treatment and further investigation was required. Her 5-oxoproline level was 3815 mmol/mol creatinine in urine organic acid analysis, and a homozygous mutation [p.R125H (c.374G>A)] was found in the glutathione synthetase gene. CONCLUSIONS: GSD has been observed in very few patients and is rarely considered in the differential diagnosis of hemolytic anemia in newborns.

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.

Cytogenetic damage of radiotherapy in long-term head and neck cancer survivors.

PURPOSE: To evaluate cytogenetic damage of radiotherapy (RT) and chemoradiotherapy (CRT) in long-term head and neck cancer survivors. MATERIALS AND METHODS: This study included 20 patients treated with RT (10 patients) or CRT (10 patients) for head and neck cancer. Nine healthy volunteers were included as control subjects. Cytochalasin B-blocked micronucleus (CBMN) assay was used to evaluate cytogenetic damage. To evaluate micronucleus (MN) by CBMN, the venous blood samples were drawn median 68 months (range 60-239 months) after the completion of treatment (RT or CRT) for head and neck cancer. RESULTS: Nuclear division index (NDI) and number of MN in mononuclear and binuclear lymphocytes were significantly higher in patients with head and neck cancer than in control subjects [1.19 (1.08-1.47) vs. 1.07 (1.04-1.14), p < 0.001; 11.0 (2.0-22.0) vs. 1.0 (0-3.0), p < 0.001 and 15.0 (5.0-45.0) vs. 9.0 (2.0-15.0), p = 0.020, respectively]. NDI and number of MN in mononuclear lymphocytes were significantly lower in control subjects compared patients received CRT and those received only RT, but there was no significant difference between patients received CRT and those received only RT. Number of MN in binuclear lymphocytes was significantly lower in control subjects compared to patients received CRT, but there was no significant difference between control subjects and those received only RT. Also there was no significant difference between patients received CRT and those received only RT in terms of number of MN in binuclear lymphocytes. CONCLUSIONS: MN frequency of mononuclear and binuclear lymphocytes in medical follow-up of patients with head and neck cancer after RT could be important in evaluating cytogenetic damage of RT. However, further investigations are needed to provide quantitative correlations between MN yields and the clinical features in post-radiotherapy period.

Combination of two different homozygote mutations in Pompe disease.

Pompe disease (OMIM no 232300) is an autosomal recessive inherited metabolic disorder, caused by glycogen accumulation in the lysosome due to deficiency of the lysosomal acid 03B1-glucosidase enzyme. Here we report the case of an 8-month-old girl of consanguineous Turkish parents, who was diagnosed with the infantile form of Pompe disease. Two different uncommon homozygote mutations (c.32-13 T > G homozygote and c.1856G > A homozygote) were detected. The patient had a more progressive clinical course than expected. We emphasize the rare combination of genetic mutations in this Turkish family with Pompe disease.