High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

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.

TUBB8 mutations as a cause of oocyte maturation abnormalities: presentation of oocyte and embryo profiles and novel mutations.

RESEARCH QUESTION: What are the embryonic profiles and oocyte maturation dynamics in patients with tubulin beta eight class VIII (TUBB8) mutations leading to oocyte maturation abnormalities (OMAS), and are pregnancies possible in this population? DESIGN: A prospective cohort study was undertaken in a private fertility clinic between January 2019 and December 2022. Whole-exome genomic studies (WES) were performed to detect mutation types. In-vitro maturation (IVM) was compared in 18 subjects: nine with TUBB8 mutations, and nine without TUBB8 mutations to act as the control group. The distributions of oocyte maturation and embryonic development profiles were recorded. IVF and IVM outcomes of the 18 cases were evaluated. The primary outcomes were the embryonic profiles and maturation dynamics of oocytes derived from IVF or IVM in women as related to TUBB8 mutations. RESULTS: Mutations were detected in 52 of 89 (58.4%) women who underwent WES analysis. Twelve TUBB8 mutations were detected in nine women (10.1%) with OMAS. Seven novel TUBB8 mutations were noted. Two pregnancies were obtained in women with c.535 G>A TUBB8 mutations. When comparing IVM outcomes between women with and without TUBB8 mutations, there were no differences in oocyte, embryo or pregnancy parameters (P>0.05 in all cases). CONCLUSIONS: It is clear that further TUBB8 mutations which cause oocyte or embryonic arrest will be detected in future. Although biochemical or ectopic pregnancies may be possible in some of these women, no live births or ongoing pregnancies have been reported to date.

Clock 3111 T/C and Period3 VNTR gene polymorphisms and proteins, and melatonin levels in women with infertility.

PURPOSE: One of the causes of infertility is circadian rhythm disorders. This study aimed to investigate Clock 3111 T/C and Period3 VNTR (variable number tandem repeat) gene polymorphisms and these gene proteins, some biochemical parameters, and circadian rhythm hormones in infertile women. METHODS: Thirty-five infertile women and thirty-one healthy fertile women were included. Blood samples were taken in the mid-luteal phase. DNAs obtained from peripheral blood were analyzed using polymerase chain reaction-restriction fragment length polymorphism methods. Follicle-stimulating hormone, LH (luteinizing hormone), estradiol, prolactin, free triiodothyronine, fT4 (free thyroxine), thyroid-stimulating hormone, testosterone, cortisol, progesterone, prolactin, ferritin, vitamin B12, and folate levels in serum samples were determined by the electrochemiluminescence immunoassay method. Melatonin, Clock, and Period3 protein levels were determined with ELISA kits. RESULTS: There was a significant difference in the frequency of Period3 DD (Per34/4) genotype between the groups. The Clock protein level of the infertile group was higher than the fertile group. Clock protein levels of the fertile group were positively correlated with estradiol levels and negatively correlated with LH, prolactin, and fT4 levels. PER3 protein levels of the infertile group were negatively correlated with LH levels. Melatonin levels of the fertile group were positively correlated with progesterone levels and negatively correlated with cortisol levels. Melatonin levels of the infertile group were positively correlated with LH levels and negatively correlated with cortisol levels. CONCLUSION: Per34/4 genotype may be an independent risk factor in infertile women. Different correlation results found in fertile and infertile women can form the basis for future studies.

Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

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.

Assessment of vaginal and endometrial microbiota by real-time PCR in women with unexplained infertility.

AIM: Microbiota of the reproductive tract may be associated with unexplained infertility in women. We aimed to determine the derangements of vaginal and endometrial microbiota related to unexplained infertility by real-time polymerase chain reaction (real-time PCR) microbiota analyses of vaginal and endometrial samples of the unexplained infertility patients and fertile women. MATERIALS AND METHODS: Twenty-six women with unexplained infertility and 26 age-matched fertile women were included. Vaginal and endometrial samples were obtained in the mid-menstrual cycle for analysis by quantitative real-time PCR method. RESULTS: The proportion of lactobacilli-impaired microbiota was significantly higher in the vaginal samples of unexplained infertility patients (76.9% vs. 26.9%; p < 0.001). Those with impaired lactobacilli microbiota of vaginal samples had an increased risk of 9.048 times for infertility than those with normal lactobacilli microbiota. In addition, the mean lactobacilli/total bacterial mass (TBM) ratio in the vaginal samples was significantly lower in the unexplained infertility patients (38.2% vs.76.3%; p = 0.001). CONCLUSION: The present study results supported the role of vaginal and endometrial microbiota derangements in unexplained infertility. Many time-consuming and invasive methods are currently used in the diagnosis of infertility. Our study showed that the quantitative determination of lactobacilli/TBM ratio in vaginal specimens, a less invasive and easily obtainable method, could be used as a diagnostic test during the workup of couples with unexplained infertility.

Derangements of vaginal and cervical canal microbiota determined with real-time PCR in women with recurrent miscarriages.

Balanced vaginal microbiota and, as a continuum, cervical canal microbiota help prevent reproductive disorders, including recurrent miscarriage (RM). In a significant proportion of couples with RM, routine diagnostic workup cannot find any manageable cause, leading to a requirement for new diagnostic tools. In the present study, we determined the quantitative composition of the microbiota of the vagina and cervical canal, assessed by real-time polymerase chain reaction, in women with RM. It also evaluated their derangements related to the pathogenesis of RM, and thus the suitability of this test as a diagnostic tool for managing RM. Vaginal and cervical canal specimens of 25 women with RM and 25 healthy volunteers were collected. The test results revealed information about the total vaginal bacterial biomass by measuring the abundance of Lactobacillus spp.; other bacteria; and pathogens, including Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma (urealyticum + parvum), and Candida spp. Overall, the findings of this study implied the abundance of Lactobacillus spp. decreased in women with RM with an increase in the abundance of other microorganisms in accordance with the reduction in the abundance of Lactobacillus spp. due to aerobic vaginitis and bacterial vaginosis. Vaginal and cervical canal microbiota need to be considered during the diagnostic workup of women with RM.IMPACT STATEMENTWhat is already known on this subject? Recurrent miscarriage (RM) is a well-known reproductive disorder. Its diagnostic workup is not successful in determining the underlying problem in many cases. Hence, novel diagnostic tools based on real-time polymerase chain reaction (PCR) are needed for evaluating reproductive microbiota, which are considerably reliable, to satisfy the expectations of women with RM.What do the results of this study add? Overall, the decrease in the abundance of Lactobacillus spp. was found to be related to RM, and the patterns of the presence of other microorganisms were in accordance with the reduction in the abundance of Lactobacillus spp. These findings suggested an important role of vaginal and cervical canal microbiota in the pathogenesis of RM.What are the implications of these findings for clinical practice and/or further research? Additional research is warranted to elucidate the functional impact of altered components of the microbiota of vaginal and cervical canals on the physiology of the local cervical canal and its participation in the microbiota of the endometrial cavity, especially regarding unsuccessful pregnancies as a result of the disturbed physiology of the local endometrial microenvironment. However, possible applications of real-time PCR-based tests for the screening of subclinical infections in clinical practice require the performance of further investigations in patients with RM.

MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine (Hcy) metabolism. We aimed to evaluate a possible relationship between MTHFR gene C677T (rs 1801133), A1298C (rs 1801131) variants and susceptibility to FMF in a Turkish cohort. MATERIAL-METHODS: This case-control study included 198 Turkish FMF patients and 100 healthy subjects as controls. MTHFR C677T and A1298C were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. RESULTS: The genotype distribution and allele frequency of the MTHFR C677T were statistically different between the patients and the control group (P=.006, P=.001, respectively). The frequency of the TT genotype and T allele of MTHFR C677T was significantly higher in the patients than in the controls. The genotype distribution of MTHFR A1298C variant did not show any statistically significant difference between the patients and the controls (P>.05). The patients had statistically different frequencies in allele C of MTHFR A1298C variant compared with the control (P=.032). We also examined the risk associated with inheriting the combined genotypes for the two MTHFR variants. According to these results, individuals who were CC homozygous at C677T locus and AA homozygous at A1298C locus have a lower risk of developing FMF (P=.002). Individuals who were TT homozygous at C677T locus and AC heterozygous at A1298C locus have higher risk of developing FMF (P=.033). CONCLUSION: Our findings clearly showed there was an association the MTHFR C677T/A1298C variants and susceptibility to FMF in the Turkish sample.

Association between colchicine resistance and vitamin D in familial Mediterranean fever.

Although colchicines are the only effective treatment of familial Mediterranean fever (FMF), resistance to colchicines (CR) which is observed in up to 30% of the patients is still a problem. Clinically, resistance to colchicine is defined as three or more attacks within the last 6 months period while using ≥2 mg/day colchicine. Previous studies have shown decreased vitamin D levels in FMF patients compared with healthy controls. The aim of this study is to evaluate whether vitamin D levels differ between CR and non-CR FMF patients. This study included 64 FMF patients who were being followed in Nephrology Clinic of Samsun Research and Education Hospital for at least 1 year. FMF was diagnosed according to the criteria defined by Livneh et al. Serum 25-hydroxy vitamin D (25-OHD) concentration (ng/mL) was detected in all FMF patients who were not in an acute attack period. From 64 patients 29 were accepted as CR. Mean 25-OHD level was 9.39 ± 1.00 ng/mL in CR patients and 18.48 ± 1.09 ng/mL in colchicine responsive patients (p < 0.001). Plasma vitamin D levels were significantly lower in colchicine resistant patients. Vitamin D deficiency may be a factor in etiopathogenesis of CR. Studies in larger patient samples that particularly evaluate the response to vitamin D replacement in CR FMF patients are needed.

Effect of vitamin D receptor gene BsmI polymorphism on hospitalization of SARS-CoV-2 positive patients.

Low vitamin D levels and adverse effects have been reported in SARS-COV-2 positive patients. This study examined the effect of the vitamin D receptor gene BsmI polymorphism on SARS-COV-2 positive patients. A total of 80 SARS-COV-2 positive inpatients were included in the study, and 110 healthy individuals were included as a control group. The 25-(OH) vitamin D3, lymphocyte, and activated partial thromboplastin time levels of SARS-COV-2 positive patients were lower than those of the control group. The prothrombin time (PT), international normalized ratio (INR), D-dimer, C-reactive protein (CRP), procalcitonin, and ferritin levels of SARS-COV-2 positive patients were higher than those of the control group. A negative correlation was found between 25-(OH) vitamin D3 levels and white blood cell count, PT, INR, D-dimer, CRP, procalcitonin, and ferritin levels in SARS-COV-2 positive patients. The 25-(OH) vitamin D3 level in individuals with the BB genotype was higher than the 25-(OH) vitamin D3 level in individuals with the Bb and bb genotype. A statistically significant difference was found between the groups in terms of the genotype and allele distributions of BsmI polymorphism. When the genotypes were analyzed in terms of bb versus Bb + BB, a statistically significant difference was found between the groups. However, this finding was not found between the intensive care inpatient subgroup and the other inpatient subgroup. In conclusion, BsmI b allele and bb genotype were associated with hospitalization for SARS-COV-2 infection. This may be because individuals with b allele have low levels of vitamin D.

Evaluating interleukin-6 levels and the rs1800795 variant in Turkish patients with COVID-19: a prospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a multisystem disease of global significance. Interleukin (IL)-6 is a soluble cytokine with a pleiotropic effect on inflammation and the immune response. OBJECTIVES: Investigate the relationship between the interleukin 6 (IL6) rs1800795 variant and IL6 level in Turkish patients with COVID-19 disease. DESIGN: Prospective cohort study. SETTING: Tertiary care hospital. PATIENTS AND METHODS: Real-time polymerase chain reaction (RT-PCR)-positive and/or chest computerized tomography (CT) scan-compatible COVID-19 patients were enrolled in the study. The clinical data and whole blood samples were collected from April 1, 2020, to August 1, 2020. IL6 rs1800795 genotyping was performed by the PCR-restriction fragment-length polymorphism (RFLP) method in 148 patients. Serum IL-6 concentrations were measured using the ELISA method in 89 patients. We evaluated the patients in three groups: asymptomatic, symptomatic, and intensive care unit patients. MAIN OUTCOME MEASURES: IL6 rs1800795 genotype frequencies and serum IL-6 levels in COVID-19 patients with different clinical presentations. SAMPLE SIZE: 148 cases. RESULTS: IL6 rs1800795 GG genotype and G allele frequency increased in PCR positive patients compared to PCR-negative patients (p ˂ 0.000). IL6 rs1800795 GC genotype and C allele frequency were lower in PCR-positive patients than in PCR-negative patients. IL6 rs1800795 GG genotype and G allele frequency were higher in asymptomatic patients than in the symptomatic and intensive care unit groups. The IL6 rs1800795 C allele frequency was lower in asymptomatic patients than in the symptomatic and intensive care unit groups. IL6 rs1800795 GG genotype and G allele frequency were higher in CT negative patients than CT positive patients, while IL6 GC genotype and C allele frequency were higher in CT positive patients than negative patients. IL6 level elevation was seen in the asymptomatic patients compared to the symptomatic and intensive care unit groups. CONCLUSIONS: These findings suggest that IL6 rs1800795 may contribute to the susceptibility of COVID-19 in people to Turkish origin. LIMITATIONS: Further large-scale studies in different genetic populations are needed as this is a single-center, prospective study.

Association of MIF-173G/C, IL-4 VNTR, and IL-1RA VNTR variants with FMF-related amyloidosis in a Turkish cohort.

The most important complication of familial Mediterranean fever (FMF) is secondary amyloidosis. The aim of this study is to investigate the risk of developing FMF-related amyloidosis with macrophage migration inhibitory factor (MIF), interleukin 4 (IL-4), and IL-1 receptor antagonist (IL-1RA) variants. This study included 62 FMF patients with amyloidosis, 110 FMF patients without amyloidosis, and 120 controls. The clinical information of the patient groups was compared. MIF-173G/C, IL-4 variant number tandem repeat (VNTR), and IL-1RA VNTR variants were analyzed for all participants. The use of colchicine, pleurisy, and appendectomy was more common in FMF patients with amyloidosis than in FMF patients without amyloidosis. MIF-173G/C C/C genotype and C allele were higher in both patient groups compared to controls. IL-1RA VNTR A1/A2 and A1/A4 genotypes and A1-A4 alleles were more common in both patient groups than controls. The IL-4 VNTR P1 allele was more common in FMF patients with amyloidosis compared to controls. The MIF-173G/C allele and the IL-1RA VNTR A1-A4 allele are associated with FMF in the Turkish population but not with amyloidosis risk in FMF patients. The IL-4 VNTR P1 allele is more common in FMF patients with amyloidosis than in healthy individuals.

Vascular endothelial growth factor gene insertion/deletion polymorphism is associated with Vitamin D level in Turkish patients with coronavirus disease 2019.

OBJECTIVE: Coronavirus disease 2019 emerges as a disease caused by severe acute respiratory syndrome coronavirus 2. It is a systemic disease associated with vascular inflammation and endothelial damage. In this study, we aimed to investigate whether vascular endothelial growth factor gene insertion/deletion polymorphism is associated with coronavirus disease 2019 in the Turkish population. METHODS: The study included 179 participants (79 patients with coronavirus disease 2019 and 100 controls). DNA isolation was made from peripheral blood, and then the polymerase chain reaction analysis was performed. RESULTS: When we analyze vascular endothelial growth factor gene insertion/deletion polymorphism in the study group, we found that the DD genotype and D allele were found to be statistically significantly different when compared to coronavirus disease 2019 patients with high vitamin D value (p=0.005 for DD genotype and p=0.006 for D allele) in the control group. In this high-level control group, when we analyze II+ID genotype versus DD, a statistically significant difference was also detected (p=0.007). CONCLUSION: As a result of the study, we found that DD genotype and D allele were associated with vitamin D level in Turkish patients with coronavirus disease 2019.

The effect of a 18 bp deletion/insertion variant of VEGF gene on the FMF development.

Objective: Familial Mediterranean fever (FMF) is one of the most common inherited autoinflammatory diseases. Angiogenesis is a feature of inflammatory activation and part of pathogenic processes in autoimmune diseases. Therefore, this study aimed to investigate the role of the Vascular endothelial growth factor (VEGF) gene insertion/deletion (I/D) functional variant in FMF Turkish patients. Methods: MEFV gene mutations were detected in all patients. The FMF patients (N:105) and the healthy controls (N:100) were genotyped for the VEGF I/D variant using PCR followed by agarose gel electrophoresis. The results were statistically analyzed by calculating the odds ratios (OR) and their 95% confidence intervals (95% CI) using the χ2-tests. Results: The mean age of patients was 25.46 ± 10.09. Fifty-nine patients (56.2%) had two or more MEFV gene mutations. The most common MEFV mutation was M694V/M694V. The VEGF I/D variant genotype distribution exhibited a statistically significant difference between the patients and the controls. VEGF I/D genotype was higher in controls compared to patients, while D/D genotype was higher in patients compared to the controls (p = 0.003, p = 0.013, respectively). When we examined the clinical findings, joint pain was more common in patients with VEGF D/D and I/D genotypes compared to I/I genotype (p = 0.043). Although not statistically significant, the most common genotype in patients with two or more MEFV mutations was VEGF D/D (28.6%). Conclusion: The results provided evidence supporting that the D/D genotype of the VEGF I/D variant is associated with an increased risk of FMF in a group of Turkish populations.

YIF1B-related Kaya-Barakat-Masson Syndrome: Report of a new patient and literature review.

Kaya-Barakat-Masson syndrome (KABAMAS) is a recently identified severe neurodevelopmental disorder characterized by severe global developmental delay, epilepsy, movement disorder, epilepsy, and microcephaly. KABAMAS is caused by bi-allelic variants in the YIF1B gene which encodes a trafficking protein involved in the anterograde traffic from the endoplasmic reticulum to the cell membrane including neural cells in association with other trafficking proteins and also Golgi apparatus morphology. That's why clinical overlapping between KABAMAS and golgipathies isn't surprising. It is a rare condition with only 24 patients reported to date. Here we described a 5.5-year-old boy presenting with severe global developmental delay, epileptic encephalopathy, microcephaly, dystonia, spasticity, blindness, feeding difficulties, respiratory failure, and dysmorphic features. Whole exome sequencing identified homozygous splice site variation (NM_001039672.3: c.297+1G > A) in the YIF1B gene. This splice site variant is rare in the general population (gnomAD Variant allele fraction (VAF): 0.0007%, 2 heterozygotes, 0 homozygotes) and has not previously been associated with the disease. Multiple in silico tools predict a deleterious effect of this splice site change. Considering the points mentioned above, we have considered the detected variant as pathogenic according to guidelines in light of current knowledge. By reporting a new case with the homozygous YIF1B splice site variant we provide further evidence to clinical and molecular data of this recently recognized severe neurodevelopmental disorder. We further emphasize that trafficking errors should be considered as an underlying mechanism in undiagnosed severe neurodevelopmental disorders.

Oocyte maturation abnormalities - A systematic review of the evidence and mechanisms in a rare but difficult to manage fertility pheneomina.

A small proportion of infertile women experience repeated oocyte maturation abnormalities (OMAS). OMAS include degenerated and dysmorphic oocytes, empty follicle syndrome, oocyte maturation arrest (OMA), resistant ovary syndrome and maturation defects due to primary ovarian insufficiency. Genetic factors play an important role in OMAS but still need specifications. This review documents the spectrum of OMAS and to evaluate the multiple subtypes classified as OMAS. In this review, readers will be able to understand the oocyte maturation mechanism, gene expression and their regulation that lead to different subtypes of OMAs, and it will discuss the animal and human studies related to OMAS and lastly the treatment options for OMAs. Literature searches using PubMed, MEDLINE, Embase, National Institute for Health and Care Excellence were performed to identify articles written in English focusing on Oocyte Maturation Abnormalities by looking for the following relevant keywords. A search was made with the specified keywords and included books and documents, clinical trials, animal studies, human studies, meta-analysis, randomized controlled trials, reviews, systematic reviews and options written in english. The search detected 3,953 sources published from 1961 to 2021. After title and abstract screening for study type, duplicates and relevancy, 2,914 studies were excluded. The remaining 1,039 records were assessed for eligibility by full-text reading and 886 records were then excluded. Two hundred and twenty seven full-text articles and 0 book chapters from the database were selected for inclusion. Overall, 227 articles, one unpublished and one abstract paper were included in this final review. In this review study, OMAS were classified and extensively evaluatedand possible treatment options under the light of current information, present literature and ongoing studies. Either genetic studies or in vitro maturation studies that will be handled in the future will lead more informations to be reached and may make it possible to obtain pregnancies.

Genetic Management Algorithm in High-Risk Fabry Disease Cases; Especially in Female Indexes with Mutations.

BACKGROUND: Fabry Disease (FD, OMIM#301500) is a progressive, life-threatening, multisystemic, rare lysosomal storage disease. Today, approximately 1000 mutations are recorded in the Human Gene Mutation Database (www.hgmd.org) for GLA. Among the identified mutations, genetic variants of unknown significance (GVUS) and novel mutations cause problems in terms of diagnosis and treatment approach. METHODS: In our study, 510 high-risk patients were enrolled. 229 out of 510 were Male (45%) (Mean age was 40.8 ±15.0) and 281 of were Female (55%) (Mean age was 39, 7±15.5). The definite diagnosis of the FD was confirmed by GLA gene sequence analysis. GLA mutation was found in 15 cases (3.4%). Family members of the relevant indexes were included in the screening programs according to the X-linked inheritance pattern. And then we conducted family screening on 74 family members of 15 index cases. Of those 74 cases, 39 had mutations (53%). In males, α-GalA activity and in both gender Lyso-Gb3 levels were measured and multisystem evaluation was performed in all cases with the mutation. RESULTS: We found six different familial mutation types; two of them pathogenic; p.D170N (1), p.P205S (13), one of them GVUS; p.Q330R (1), three of them likely benign; p.D313Y (12), p.S126G (25), c.-30G>A (2) mutations were detected. CONCLUSION: The purpose of this retrospective study is to approach Fabry disease on a genetic basis and to improve its management and to draw attention to the importance of early diagnosis. We also aimed to evaluate the appropriate algorithms to determine whether the mutation is the FD-causing mutation or not.

Angiotensin-converting enzyme-1 gene insertion/deletion polymorphism may be associated with COVID-19 clinical severity: a prospective cohort study.

BACKGROUND: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism may play a role in the pathogenesis of coronavirus-19 disease (COVID-19). OBJECTIVES: Investigate the relationship between ACE I/D polymorphism and the clinical severity of COVID-19. DESIGN: Prospective cohort study. SETTING: Tertiary care hospital. PATIENTS AND METHODS: The study included COVID-19 patients with asymptomatic, mild, and severe disease with clinical data and whole blood samples collected from 1 April 2020 to 1 July 2020. ACE I/D genotypes were determined by polymerase chain reaction and agarose gel electrophoresis. MAIN OUTCOME MEASURE: ACE DD, DI and II genotypes frequencies. SAMPLE SIZE: 90 cases, 30 in each disease severity group. RESULTS: Age and the frequency of general comorbidity increased significantly from the asymptomatic disease group to the severe disease group. Advanced age, diabetes mellitus and presence of ischemic heart disease were independent risk factors for severe COVID-19 [OR and 95 % CI: 1.052 (1.021-1.083), 5.204 (1.006-26.892) and 5.922 (1.109-31.633), respectively]. The ACE II genotype was the dominant genotype (50%) in asymptomatic patients, while the DD genotype was the dominant genotype (63.3 %) in severe disease. The ACE II geno-type was protective against severe COVID-19 [OR and 95% CI: .323 (.112-.929)]. All nine patients (8.9%) who died had severe disease. CONCLUSIONS: The clinical severity of COVID-19 infection may be associated with the ACE I/D polymorphism. LIMITATIONS: Small sample size and single center. CONFLICT OF INTEREST: None.