Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes.

Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic/likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in four fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first-line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

The morbid genome of ciliopathies: an update.

PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

Isosorbide Mononitrate Versus Dinoprostone for Cervical Ripening During Labor Induction: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

The objective of this study was to conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated isosorbide mononitrate (ISMN) versus dinoprostone, a prostaglandin E2 (PGE2) analogue, in promoting cervical ripening during labor induction. We searched five major databases from inception till 02 May 2021. We assessed the risk of bias of included studies. We meta-analyzed various endpoints (n=12) and pooled the endpoints as mean difference (MD) or risk ratio (RR) with 95% confidence interval (CI). Overall, 4 RCTs met the inclusion criteria, comprising 818 patients; equally 409 patients were allocated to ISMN and PGE2 groups. Overall, the RCTs had a low risk of bias. The mean change in Bishop score at 24 h was significantly lower in disfavor of the ISMN group. The mean time from drug administration to delivery was significantly longer in disfavor of the ISMN group. The rate of oxytocin need was significantly higher in disfavor of the ISMN group. The rate of vaginal delivery at 24 h was significantly lower in disfavor of the ISMN group. The rates of headache and palpitations were significantly higher in disfavor of the ISMN group. The rate of abnormal fetal heart rate was significantly lower in favor of the ISMN group. There was no significant difference between both groups with regard to rates of cesarean delivery, postpartum hemorrhage, uterine hyperstimulation, and NICU admission. Compared with PGE2, ISMN appeared less effective for cervical ripening prior to labor induction and correlated with higher drug-related maternal toxicities.

Misoprostol plus isosorbide mononitrate versus misoprostol alone for cervical ripening during labor induction: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that examined the maternal and neonatal outcomes of misoprostol+isosorbide mononitrate (ISMN) versus misoprostol alone (control) in promoting cervical ripening during labor induction. METHODS: We searched five databases from inception until 05-May-2021. We assessed risk of bias of RCTs, meta-analyzed 23 endpoints, and pooled them as mean difference or risk ratio with 95% confidence interval. RESULTS: Overall, five RCTs met the inclusion criteria, comprising 850 patients (426 and 424 patients were allocated to misoprostol+ISMN and misoprostol group, respectively). Overall, the RCTs had a low risk of bias. Pertaining to maternal delivery-related outcomes, there was no significant difference between both groups regarding the mean interval from drug administration to delivery, rate of vaginal delivery, rate of cesarean section delivery, and rate of need for oxytocin augmentation. Pertaining to maternal drug-related side effects, the rate of maternal headache was significantly higher in disfavor of the misoprostol+ISMN compared with misoprostol alone. However, the rates of maternal nausea, hypotension, flushing, palpitation, dizziness, postpartum hemorrhage, and uterine tachysystole did not differ between both groups. Pertaining to neonatal outcomes, there was no significant difference between both groups regarding rates of NICU admission, meconium-stained amniotic fluid, and Apgar score <7 at five minutes. CONCLUSION: Compared with misoprostol alone, co-administration of misoprostol+ISMN did not correlate with superior maternal delivery-related outcomes. The rate of maternal headache was significantly higher in disfavor of the misoprostol+ISMN group. There was no significant difference between both groups regarding neonatal endpoints.

Isosorbide mononitrate for cervical ripening during labour induction: A systematic review and meta-analysis of 23 randomized controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated the efficacy and safety of isosorbide mononitrate (IMN) in promoting cervical ripening during labour induction. METHODS: Six major databases were searched from inception until 22 April 2021. The risk of bias of included studies was assessed. Various endpoints (n = 21) were meta-analysed, and the endpoints were pooled as mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI). RESULTS: In total, 23 RCTs were included in this review, comprising 26 intervention arms and a total of 4305 patients (2210 and 2095 patients were allocated to the IMN and control groups, respectively). Pertaining to obstetric-related maternal outcomes, the pooled analysis showed that admission to delivery time and rate of caesarean delivery were significantly reduced in the IMN group. Moreover, the mean Bishop score and the mean change in Bishop score were significantly increased in the IMN group. Pertaining to drug-related maternal side effect outcomes, the pooled analysis showed that the rates of headache, palpitations, nausea and flushing were significantly lower in the IMN group. Pertaining to neonatal outcomes, the pooled analysis showed no significant difference between the two groups in terms of the rates of neonatal intensive care unit admission, neonatal death, fetal distress, meconium-stained water, Apgar score < 7 at 1 and 5 min, and mean Apgar score at 1 and 5 min. CONCLUSION: IMN correlated with several obstetric-related maternal outcomes. IMN was not associated with adverse neonatal outcomes, but was associated with substantial drug-related maternal side effects.

Prophylactic tranexamic acid among women undergoing vaginal delivery to reduce postpartum blood loss and related morbidities: A systematic review and meta-analysis of 17 randomized controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that inspected the efficacy and safety of prophylactic TXA compared with control (placebo/no treatment) among women undergoing vaginal delivery on reducing postpartum blood loss and related morbidities. METHODS: Six databases were screened from inception until 06-December-2021. The pooled data were summarized as mean difference or risk ratio, respectively, with 95% confidence interval in a fixed- or random-effects model. RESULTS: Sixteen studies comprising 17 RCT treatment arms were included. There were 7122 patients; 3611 and 3511 patients were allocated to prophylactic TXA and control groups, respectively. Overall, the included RCTs had a low risk of bias. Prophylactic TXA correlated with a significant decrease in mean postpartum blood loss and mean change in hemoglobin/hematocrit. Moreover, prophylactic TXA was linked to decreased incidence rates of postpartum hemorrhage, need for blood transfusion, and need for additional uterotonic agents. Nevertheless, prophylactic TXA culminated in significantly higher incidence rates of nausea, vomiting, and diarrhea, all of which were well-tolerated. There was no increased risk of thromboembolic events. Leave-one-out sensitivity analysis confirmed the robustness of efficacy endpoints. There was no publication bias for the endpoint of mean postpartum blood loss. CONCLUSION: Among patients undergoing vaginal delivery, prophylactic TXA during active management of third stage of labor (AMTSL) appeared largely safe and correlated with a significant decrease in postpartum blood loss and related morbidities compared with control intervention. Prophylactic TXA should be integrated as a "formal" component of AMTSL among women undergoing vaginal delivery.