Prenatal diagnosis of Sex determining region Y -box transcription factor 2 anophthalmia syndrome caused by germline mosaicism using next-generation sequencing: A case report

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

The imbalance in expression of angiogenic and anti-angiogenic factors as candidate predictive biomarker in preeclampsia

Preeclampsia is an important pregnancy disorder with serious maternal and fetal complications which its etiology has not been completely understood yet. Early diagnosis and management of disease could reduce its potential side effects. The vascular endothelial growth factor (VEGF) family including VEGF-A is the most potent endothelial growth factor which induces angiogenesis and endothelial cell proliferation and has basic role in vasculogenesis. VEGF and its tyrosine kinase receptors (Flt1 and KDR) are major factors for fetal and placental angiogenic development. Finding mechanisms involved in expression of angiogenic factors may lead to new prognostic and therapeutic points in management of preeclampsia. Recent researches, has shown capability of some anti-angiogenic factors as potential candidate to be used as early predictors for preeclampsia. Soluble fms-like tyrosin kinase-1 (sFlt1) is a truncated splice variant of the membrane-bound VEGF receptor Flt1, that is produced by the placenta and it can bind to angiogenic growth factors and neutraliz, their effects. It is also observed that the ratio of sFlt1 to placental growth factor is valuable as prognostic marker. In this review, VEGF family member’s role in angiogenesis is evaluated as biomarkers to be used for prediction of preeclampsia

Effect of predictive value of progesterone level on the day of HCG injection for IVF success in women with infertility due to tubal factor or polycystic ovarian syndrome referred to the women hospital, Tehran, 2009

Background: Polycystic ovarian syndrome is one of the most common causes of endocrine disorders and main reason of infertility due to anovulation and recurrent abortions. Progesterone has been shown to have an important role in fertilization of oocyte and fetal implantation. Objective: The purpose of this study was to compare the predictive value of progesterone level on IVF success in women with infertility due to tubal factor or PCOS. Materials and Methods: In a stratified cohort study, we assigned 76 infertile women of 20-38 years old who referred to women hospital into two equal groups with fallopian tube factor infertility and PCOS. We measured the plasma levels of progesterone and estradiol on the day of HCG administration. The patients were divided into two groups based on progesterone level cut off point of 1.2ng/ml. Thereafter the incidence of pregnancy (chemical by β-HCG measurement and clinical by ultrasonography up to the 6 weeks after fetal transfer) was compared in these groups. Results: Total pregnancy rates were 15.8% in patients with tubal factor infertility and 26.3% in women with PCOS. In women with PCOS, the pregnancy rate was less in patients with progesterone level <1.2 ng/ml. However this difference was not statistically significant. Likewise, we did not observe any significant differences in pregnancy rate in patients with fallopian tube factor infertility. Conclusion: Serum progesterone level on the day of HCG administration is not well predictive of the IVF success in infertile women due to fallopian tube factor or PCOS. To obtain more uniform results, we recommend use of larger samples while the bias variable is taken into account and the ROC curve is used for determination of the unique serum progesterone level

Increased expression level of Dicer in placenta is associated with the early onset of preeclampsia

This is a Letter to the Editor and does not have an abstract

Pre-implantation genetic diagnosis in an Iranian family with a novel mutation in MUT gene

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

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

Purpose: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. Methods: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. Results: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. Conclusion: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder