Identification of disease-causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next-generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.     

The effect of nettle (Urtica dioica) supplementation on the glycemic control of patients with type 2 diabetes mellitus: A systematic review and meta‐analysis

Type 2 diabetes mellitus (T2DM) is a major health problem, worldwide, that is associated with increased morbidity and mortality. Several randomized controlled clinical trials (RCTs) have investigated the effect of nettle (Urtica dioica) supplementation on markers of glycemic status in patients with T2DM, with conflicting results. Therefore, the present study assessed the effect of nettle on some glycemic parameters in patients with T2DM. A comprehensive search was conducted in PubMed, Scopus, Cochrane Library, and Web of Science, from database inception up to June 2019, to identify RCTs investigating the effect of nettle supplementation on glycemic markers, including fasting blood sugar (FBS) concentrations, insulin levels, homeostasis model assessment‐estimated insulin resistance index, and glycosylated hemoglobin percentage in adults with T2DM. The Cochrane Collaboration tool was used to assess the methodological quality of the included studies. Results of this meta‐analysis were reported based on the random effects model. Eight RCTs, comprising 401 participants, were included in the present systematic review and meta‐analysis. Based on the Cochrane Collaboration risk of bias tool, five studies were considered as good quality, one was fair, and two studies were poor, respectively. The results of the meta‐analysis revealed a significant reduction in FBS concentrations (weighted mean difference [WMD]: ?18.01 mg/dl, 95% confidence interval [CI]: ?30.04 to ?5.97, p < .001, I² = 94.6%) following nettle supplementation. However, no significant reduction was observed in insulin levels (WMD: 0.83 Hedges' g, 95% CI: ?0.26 to 1.92, p = .13, I² = 89.4%), homeostasis model assessment‐estimated insulin resistance index (WMD: ?0.22, 95% CI: ?0.83 to 0.40, p = .49, I² = 69.2%), or glycosylated hemoglobin percentage (WMD: ?0.77%, 95% CI: ?1.77 to 0.22, p = .12, I² = 83.0%). The findings of the present study suggest that nettle supplementation may be effective in controlling FBS for T2DM patients. However, further studies are needed to confirm the veracity of these results.     

Reliability, comparative validity and stability of dietary patterns derived from an FFQ in the Tehran Lipid and Glucose Study

The aim of the present study was to assess the reliability, comparative validity and stability of dietary patterns defined by factor analysis for participants of the Tehran Lipid and Glucose Study. A total of 132 subjects, aged?≥?20 years, completed a 168-item FFQ (FFQ1, FFQ2) twice, with a 14-month interval. Over this duration, twelve dietary recalls (DR) were collected each month. To assess the stability of the FFQ, participants completed the third FFQ (FFQ3) after 8 years. Following these, two dietary patterns - the 'Iranian Traditional' and the 'Western' - were derived from FFQ1 and FFQ2 and the mean of DR (mDR); and three dietary patterns were identified from FFQ3: the 'Iranian Traditional', the 'Western' and the 'Combined'. The reliability correlations between factor scores of the two FFQ were 0·72 for the Iranian Traditional and 0·80 for the Western pattern; corrected month-to-month variations of DR correlations between the FFQ2 and mDR were 0·48 for the first and 0·75 for the second pattern. The 95?% limits of agreement for the difference between factor scores obtained from FFQ2 and mDR lay between -?1·58 and +1·58 for the Iranian Traditional and between -?1·33 and +1·33 for the Western pattern. The intra-class correlations between FFQ2 and FFQ3 were -?0·09 (P?=?0·653) and 0·49 (P?<0·001) for the 'Iranian Traditional' and the 'Western', respectively. These data indicate reasonable reliability and validity of the dietary patterns defined by factor analysis. Although the Western pattern was found to be fairly stable, the Iranian Traditional pattern was mostly unstable over the 8 years of the study period.     

Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.Worldwide, more than 5 million babies (Ferraretti et al. 2013) have been born through in vitro fertilization (IVF) since the birth of the first in 1978 (Steptoe and Edwards 1978). Exact numbers are difficult to determine, but it has been estimated that currently 350,000 babies are born yearly through IVF (de Mouzon et al. 2009, 2012; Centers for Disease Control and Prevention 2011; Ferraretti et al. 2013). That number is expected to rise, as advanced maternal age is associated with decreased fertility rates and women in developed countries continue to delay childbirth to later ages. In 95% of IVF procedures, no diagnostic testing of the embryos is performed (https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0). Couples with prior difficulties conceiving or those wishing to avoid the transmission of highly penetrant heritable diseases often choose to perform preimplantation genetic diagnosis (PGD). PGD involves the biopsy of one cell from a 3-d embryo or the recently more preferred method, due to improved implantation success rates (Scott et al. 2013b), of up to 10 cells from a 5- to 6-d blastocyst-stage embryo. Following biopsy, genetic analysis is performed on the isolated cell(s). Currently this is an assay for translocations and the correct chromosome copy number (Hodes-Wertz et al. 2012; Munne 2012; Yang et al. 2012; Scott et al. 2013a; Yin et al. 2013), a unique test designed and validated for each specific heritable disease (Gutierrez-Mateo et al. 2009), or a combination of both (Treff et al. 2013). Importantly, none of these approaches can detect de novo mutations.Advanced maternal age has long been associated with an increased risk of producing aneuploid embryos (Munne et al. 1995; Crow 2000; Hassold and Hunt 2009) and giving birth to a child afflicted with Down syndrome or other diseases resulting from chromosomal copy number alterations. Conversely, children of older fathers have been shown to have an increase in single base and short multibase insertion/deletion (indels) de novo mutations (Kong et al. 2012). Many recent large-scale sequencing studies have found that de novo variations spread across many different genes are likely to be the cause of a large fraction of autism cases (Michaelson et al. 2012; O’Roak et al. 2012; Sanders et al. 2012; De Rubeis et al. 2014; Iossifov et al. 2014), severe intellectual disability (Gilissen et al. 2014), epileptic encephalopathies (Epi4K Consortium and Epilepsy Phenome/Genome Project 2013), and many other congenital disorders (de Ligt et al. 2012; Veltman and Brunner 2012; Yang et al. 2013; Al Turki et al. 2014). Additionally rare and de novo variations have been suggested to be prevalent in patients with schizophrenia (Fromer et al. 2014; Purcell et al. 2014), and Michaelson et al. (2012) found that single base de novo mutations affect conserved regions of the genome and essential genes more often than regions of unknown function. Current targeted approaches to PGD would miss many of these important functional changes within the embryonic DNA sequence, and even a whole-genome sequencing (WGS)–based carrier screen of both parents would not enable comprehensive preimplantation or prenatal diagnoses due to de novo mutations. As more parents delay childbirth into their mid-30s and later, these studies suggest we should try to provide better diagnostic tests for improving the health of newborns. In this study, we demonstrate the use of an advanced WGS process that provides an accurate and phased genome sequence from about 10 cells, allowing highly sensitive and specific detection of single base de novo mutations from IVF blastocyst biopsies.     

Role of 3D sonohysterography in the investigation of uterine synechiae/asherman's syndrome: Pictorial assay

Several imaging methods have been applied for evaluation of suspected uterine synechiae; however, sonohysterography is yet recognised as a valid and accurate modality. Performing three‐dimensional (3D) imaging along with sonohysterography enables evaluation of the uterus in the coronal plane to detect and grade the adhesions that characterise this condition. Thus, 3D sonohysterography is a minimally invasive and cost‐effective tool for investigating suspected synechiae and is particularly useful when the transvaginal sonography findings are normal.     

Underutilization and clinical benefits of angiotensin-converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction

Despite evidence of therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors for congestive heart failure and asymptomatic left ventricular (LV) dysfunction, recent studies suggest that in heart failure patients, rates of ACE inhibitor usage in clinical practice remain low. In this study, the medical records of 107 patients with documented LV dysfunction were investigated for patterns of ACE inhibitor usage; 6-month and 1-year outcomes and event rates were evaluated. At index admission, 48% patients did not receive ACE inhibitor treatment, 32% were initiated on treatment, 19% continued on a prior regimen, and 1% were discontinued. Patients seen by a cardiologist were more likely to receive ACE inhibitor treatment (53% vs 35%, p = 0. 172), as were patients with histories of hypertension (60% vs 40%, p = 0.044) or myocardial infarction (56% vs 44%, p = 0.221). Significantly shorter hospitalizations (5.9 vs 9.5 days, p = 0.001) were noted for patients with on-going ACE inhibitor treatment compared with those receiving newly initiated treatment or no treatment. At time of hospital discharge, 102 patients were alive. Of 54 patients who received ACE inhibitors, 67% received an insufficient dose. At a 6-month follow-up, of 51 patients on ACE inhibitors, 23% died or were readmitted to hospital compared with 55% of nonusers (p = 0.001). At 1 year, this event rate was 31% among ACE inhibitor users versus 71% among nonusers (p < 0.0001). Bivariate and multivariate analysis revealed absence of ACE inhibitor use as the only significant variable associated with the event rate (p < 0.0011). Thus, about half of patients with asymptomatic LV dysfunction received ACE inhibitors; 2/3 of these did not receive a sufficient dose. ACE inhibitor usage increased with involvement of a cardiologist, presence of coexistent hypertension, or prior myocardial infarction. Ongoing ACE inhibitor therapy was associated with shorter hospitalizations and fewer hospital readmissions or deaths.