Preeclampsia (PE) is a serious complication of pregnancy and one of the main causes of maternal and neonatal mortality and morbidity in the world. Finding a biomarker with high sensitivity and ...specificity could lead to prediction and early diagnosis of the disease and reduces its complications. In this study, we evaluated diagnostic accuracy of Soluble fms-like tyrosine kinase-1 (sFlt-1) to Placental growth factor (PlGF) ratio for diagnosis of PE.
The cases included 23 mild, 15 severe preeclamptic patients, and 20 normal term pregnant women as control referred to GYN ward of the Persian Gulf Hospital in Bandar Abbas from 2014 to 2016. Levels of sFlt-1 and PlGF were measured. Receiver Operating Characteristic (ROC) curve analysis was applied to calculate diagnostic accuracy of sFlt-1/PlGF ratio.
The mean Level of sFlt-1/PlGF in PE patients (91.33 ng/ml) was significantly higher than control women (17.62) (P<0.001). ROC curve analysis showed sFlt-1/PlGF ratio diagnostic accuracy in preeclamptic patients with Area Under Curve (AUC) of 0.90, the best cut-off value of 24.96, sensitivity and specificity of 84.2 and 85.0%, respectively.
Our data showed sFlt-1/PlGF ratio has higher accuracy for differentiating PE patients from non-PEs in comparison with its power for differentiating severe or early onset forms of the disease.
Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian ...population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic groups. We show that Iranians, while close to neighboring populations, present distinct genetic variation consistent with long-standing genetic continuity, harbor high heterogeneity and different levels of consanguinity, fall apart into a cluster of similar groups and several admixed ones and have experienced numerous language adoption events in the past. Our findings render Iran an important source for human genetic variation in Western and Central Asia, will guide adequate study sampling and assist the interpretation of putative disease-implicated genetic variation. Given Iran's internal genetic heterogeneity, future studies will have to consider ethnic affiliations and possible admixture.
In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. ...Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near‐ and middle‐east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole‐exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6‐fold, and about 4.1 to 4.25‐fold for children of first‐cousin unions. These results do not rhyme with recent opinions that consanguinity‐related health risks are generally small and have been “overstated” in the past.
Background: Sex determining region Y box transcription factor 2 (SOX2) mutations lead to bilateral anophthalmia with autosomal dominant human inheritance. SOX2 mutations could result in severe ocular ...phenotypes usually associated with variable systemic defects. Most patients described with SOX2 anophthalmia syndrome possessed de novo mutations in this gene.
Case Presentation: In this case report, we describe 2 brothers with mental retardation and bilateral anophthalmia caused due to SOX2 germline mosaicism in unaffected parents. Next-generation DNA sequencing was carried out to determine the family’s possible cause of genetic mutation. Sanger sequencing was performed on the patients and their parents. Prenatal diagnosis was done in both pregnancies of the older brother’s wife via chorionic villus sampling. A novel heterozygous pathogenic frameshift deletion variant (exon1:c.58_80del:p.G20fs) was identified in the SOX2 gene, which was confirmed by Sanger sequencing in both affected brothers and did not exist in healthy parents, indicating germline mosaicism.
Conclusion: Most SOX2 mutations known look to arise de novo in probands and are diagnosed through anophthalmia or microphthalmia. Prenatal diagnosis should be offered to healthy parents with a child with SOX2 mutation every pregnancy.
Key words: Anophthalmos, SOX2 anophthalmia syndrome, Mosaicism.
Methylmalonic acidemia (MMA), which is an autosomal recessive metabolic disorder, is caused by mutations in methylmalonyl-CoA mutase (MUT) gene. As a result, the conversion of methylmalonyl-CoA to ...succinyl-CoA is impaired in this disorder, leading to a wide range of clinical manifestations varying from no signs or symptoms to severe lethargy and metabolic crisis in newborn infants. Since identification of novel mutations in MUT gene can help discover the exact pathogenesis of MMA and also use these disease-causing mutations in prenatal diagnosis, this study was conducted to uncover the possible mutations in an Iranian couple with a deceased offspring clinically diagnosed as having organic acidemia. Moreover, to prevent the occurrence of the mutation in the next pregnancy, we took the advantage of pre-implantation genetic diagnosis (PGD), which resulted in a successful pregnancy.
The affected individual was a 15-month-old boy who passed away due to aspiration pneumonia. The child presented at the age of 3 months with lethargy, protracted vomiting, hypotonia, and decreased level of consciousness. To find the mutated gene, Next Generation Sequencing (NGS) was performed as carrier testing for the parents and the results revealed a novel (private) heterozygous missense mutation in MUT gene (c.1055A > G, p.Q352R). After performing PGD on three blastomeres, one was identified as being homozygous wild-type that was followed by successful pregnancy.
Our study identified a novel, deleterious, heterozygous missense mutation in MUT gene in a couple and helps to consider the genetic counselling and prenatal diagnosis more seriously for this family with clinical phenotypes of organic acidemia.
The use of biomarkers for diagnosis of Preeclampsia (PE), a life-threatening pregnancy disorder, could reduce serious complications of this disease. In this study, we investigated dysregulation of ...endoglin (Eng) expression and diagnostic accuracy of soluble endoglin (sEng) in PE patients.
For this case-control study, 26 mild and 15 severe preeclamptic women along with 20 normotensive controls were recruited. The expression level of Eng (the co-receptor of TGF-β1) was evaluated using qRT-PCR. Also, the serum concentration of soluble Eng and expression of membranous Eng were determined by ELISA and immunohistochemistry.
A significant up-regulation in Eng mRNA and sEng levels was observed in PE patients versus normal controls. Immunohistochemistry (IHC) showed up-regulation of membranous Eng staining in syncytiotrophoblast and cytotrophoblast cells of PE patients. The serum levels of sEng were significantly increased in all patients (mild, sever, early- and late-onset) as compared to healthy pregnant women (P˂0.001). Receiver-operating characteristic (ROC) curve analysis revealed that sEng had the highest accuracy in distinguishing PE from normal pregnancies with cut-off value of 20.4, sensitivity of 92.1%, specificity of 90%, and area under the curve (AUC) of 0.94 (95% CI: 0.88-1.00).
Our data showed that the up-regulation of Eng mRNA along with its membranous and soluble form in PE patients leads to defect in angiogenesis pathway. Also, the results of this study revealed sEng potential as a marker for diagnosis of PE and its severity.
Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts ...of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype-phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.
Preeclampsia (PE) is a serious complication of pregnancy with hallmarks of incomplete placentation, placental ischemia and endothelial dysfunction. Imbalance between vascular endothelial growth ...factor (VEGF), placenta growth factor (PlGF) and their receptors play important role in pathophysiology of PE.
This study was aimed to asses PlGF mRNA expression in placenta of women affected with PE.
In this cross-sectional study, expression of PlGF mRNA was evaluated in 26 mild PE cases, 15 severe preeclamptic women and 20 normotensive controls. Patients were sub-classified as early onset PE (9) and late onset (32). After RNA extraction, PlGF expression was quantified with qRT-PCR.
The results of PlGF mRNA expression between mild-severe, and early-late onset PE patients showed no statistically significant difference compared with the control group (p=0.661, p=0.205 respectively).
Despite we found no distinct differential expression of PlGF mRNA in placental tissue of PE patients compared with control women, but according to decreased level of this angiogenic factor in PE even before clinical onset of the disease, determining molecular mechanisms related to reduced secretion of PlGF into the maternal circulation may be useful for future therapeutics.
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