Schaaf‐Yang syndrome (SHFYNG) is a rare pleiotropic disorder, characterized by hypotonia, joint contractures, autism spectrum disorders (ASD), and developmental delay/intellectual disability. ...Although it shares some common features with Prader‐Willi Syndrome, joint contractures, and ASD were more commonly detected in in this syndrome. Recently, it was shown that truncating variants in the paternal allele of the MAGEL2 gene cause SHFYNG. Here, we present two patients diagnosed with SHFYNG syndrome having two different novel truncating variants in the MAGEL2 gene, one paternally inherited and one de novo. One patient had obesity, brachydactyly and dysmorphic features, and the other patient presented with contractures, severe hypotonia and early death. This is the first report of Turkish SHFYNG syndrome cases presented to emphasize the phenotypic diversity of the syndrome.
Schaaf‐Yang syndrome (SHFYNG) is a rare pleiotropic disorder. Here, two patients with different phenotypic presentations, diagnosed as SHFYNG syndrome having two different novel variants in the MAGEL2 gene were presented. This is the first report of Turkish SHFYNG cases presented to emphasize the phenotypic diversity of the syndrome.
CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about ...diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in 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.
Breast cancer (BC) persists as the predominant malignancy globally, standing as the foremost cause of cancer-related mortality among women. Despite notable advancements in prevention and treatment, ...encompassing the incorporation of targeted immunotherapies, a continued imperative exists for the development of innovative methodologies. These methodologies would facilitate the identification of women at heightened risk, enhance the optimization of therapeutic approaches, and enable the vigilant monitoring of emergent treatment resistance. Circulating microRNAs (miRNAs), found either freely circulating in the bloodstream or encapsulated within extracellular vesicles, have exhibited substantial promise for diverse clinical applications. These applications range from diagnostic and prognostic assessments to predictive purposes. This study aimed to explore the potential associations between BRCA mutations and specific miRNAs (miR-21, miR-155, miR-126, and miR-200c) expression that are known to be dysregulated in BC patient samples. Our findings indicate a robust correlation between miRNA expression status and disease subtypes. We found a correlation between the expression status of miRNAs and distinct disease subtypes. Intriguingly, however, no significant associations were discerned between disease status, subtypes, or miRNA expression levels and the presence of BRCA mutations. To advance the validation of miRNAs as clinically relevant biomarkers, additional investigations within larger and meticulously selected patient cohorts are deemed imperative. These microRNA entities hold the potential to emerge as groundbreaking and readily accessible tools, poised for seamless integration into the landscape of clinical practice.
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.
Maturity-onset diabetes of the young (MODY) is a rare monogenic type of diabetes, and accounts for 2-5% of all diabetes cases. An early age of onset, a family history supporting autosomaldominant ...inheritance, insulin resistance, and the absence of autoimmunity are the major characteristics of MODY. However, genetic testing is crucial for diagnosis.
To investigate the 7 MODY-related genes and clinical findings of patients with a preliminary clinical diagnosis of MODY.
Retrospective cross-sectional study.
In this study, 7 genes (KCNJ11, ABCC8, INS, GCK, HNF4A, HNF1A, and HNF1B) related to MODY were screened via targeted sequencing in 182 cases with a confirmed pre-diagnosis of MODY. The clinical characteristics of the patients were evaluated retrospectively.
A total of 182 patients, 48% of whom were women, between the ages of 18-62 were included in the study. In 30 cases (16.4%), 28 different pathogenic variations were found, of which 20 were previously reported and 8 were novel variations segregated by disease within the family. Pathogenic variations were detected in the following genes in order of mutation frequency; GCK, HNF1A, ABCC8, HNF4A, HNF1B and KCNJ11. Interestingly, six of the 30 cases (20%) carried a pathogenic variation in the ABCC8 gene. No mutation was detected in the INS gene. A family history of vertically transmitted diabetes and elevated HbA1C at the time of diagnosis were found in 20 (66%) and 16 (52%) cases, respectively.
In this series, 28 different pathogenic variations are identified, 8 of which are novel. The rate of pathogenic variation in the ABCC8 gene is unexpectedly high. Two-thirds of cases have a family history of vertically transmitted diabetes.
Familial adenomatous polyposis (OMIM #175100) and MUTYH-associated polyposis (OMIM #608456) are rare cancerprone disorders characterized by hundreds of adenomatous polyps in the colon and rectum, ...which have a high probability of malignant transformation. Attenuated familial adenomatous polyposis is a variant of familial adenomatous polyposis, which is a term used for the condition in which patients have less than 100 colorectal polyps. Germline heterozygous Adenomatous polyposis coli (APC) and biallelic MUTYH (mutY DNA glycosylase) pathogenic variations are responsible for familial adenomatous polyposis and MUTYH-associated polyposis respectively. The aim of this study is to discuss the clinical manifestations of patients having pathogenic APC and MUTYH variations.
We included 27 probands who have more than 10 colonic polyps in this study. After evaluation of their clinical and family histories, the probands were screened for APC and MUTYH variations via next generation sequencing. The family members of the probands carrying pathogenic variations were screened via Sanger sequencing.
Among 27 probands, pathogenic APC and MUTYH variations were detected in 3 and 6 probands respectively. In the APC gene, 3 novel truncating variations (p.Leu360*, p.Leu1489Phefs*23, and p.Leu912*) were detected in 3 unrelated probands. In the MUTYH gene, only 2 distinct pathogenic variations were detected (p.Pro295Leu and p.Glu480del) in the homozygous or compound heterozygous state.
In this study, molecular etiology was clarified in 9 familial polyposis patients. The p.Pro295Leu and p.Glu480del variations seem to be common in the Turkish population and may be considered as a first-step genetic test in Turkish familial polyposis patients showing autosomal recessive inheritance. However more studies are needed to reveal the exact frequency of these variations.
Ovarian cancer (OC) is the main cause of gynecological cancer mortality in most developed countries. microRNA (miR) expression dysregulation has been highlighted in human cancers, and miR-34a is ...found to be downregulated and associated with inhibition of tumor growth and invasion in several malignancies, including OC. The winged helix transcription factor forkhead box P1 (FOXP1) is reported as either an oncogene or tumor suppressor in various cancers. This study aimed to elucidate potential clinical and biological associations of miR-34a and transcription factor FOXP1 in OC. We investigated nine OC patients’ blood samples and two OC cell lines (SKOV-3 and OVCAR-3) using quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) to determine both miR-34a and FOXP1 expressions. We have found that miR-34a and FOXP1 are reversely correlated in both in vitro and in vivo. Inhibition of miR-34a transiently led to upregulation of FOXP1 mRNA expression and increased cellular invasion in vitro. Our data indicate that miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC, and miR-34a overexpression may reduce OC pathogenesis by targeting FOXP1.
Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extra-pituitary abnormalities (syndromic hypopituitarism). A large ...number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The Forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut and pancreatic development.
To characterize two patients with syndromic hypopituitarism due to FOXA2 gene defects.
We report a novel heterozygous nonsense c.616C>T (p.Q206X) variant, which leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the GLUT2-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 megabase (Mb) deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment.
Our two cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.
Introduction: Myhre syndrome (MS; OMIM #139210) is a rare connective tissue disorder presenting with cardiovascular, respiratory, gastrointestinal, and skeletal system findings. Fewer than 100 ...patients were reported until recently, and all molecularly confirmed cases had de novo heterozygous gain-of-function mutations in the SMAD4 gene. Dysregulation of the TGF-beta signaling pathway leads to axial and appendicular skeleton, connective tissue, cardiovascular system, and central nervous system abnormalities. Case Presentation: Two siblings, 12 and 9 years old, were referred to us because of intellectual disability, neurodevelopmental delay, and dysmorphic facial features. Physical examination revealed hypertelorism, strabismus, small mouth, prognathism, short neck, stiff skin, and brachydactyly. Discussion: With a clinical diagnosis of MS, the SMAD4 gene was analyzed via Sanger sequencing, and a heterozygous c.1486C>T (p.Arg496Cys) pathogenic variation was detected in both of the siblings. The segregation analysis revealed that the mutation was inherited from the father who displayed a milder phenotype. Among the 90 patients in the literature, one family was reported in which two siblings carried the same variation (p.Arg496Cys), inherited from the severely affected mother. We are reporting the second family which has three affected family members, a father and two children. We report this study to remind the clinicians to be aware of the parental transmission of SMAD4 variations and also evaluate the parents of the Myhre cases.
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