Background: Identifying genetic variants that lead to discernible phenotypes is the core of Mendelian genetics. An approach that considers embryonic lethality as a bona fide Mendelian phenotype has the potential to reveal novel genetic causes, which will further our understanding of early human development at a molecular level. Consanguineous families in which embryonic lethality segregates as a recessive Mendelian phenotype offer a unique opportunity for high throughput novel gene discovery as has been established for other recessive postnatal phenotypes. Results: We have studied 24 eligible families using autozygosity mapping and whole-exome sequencing. In addition to revealing mutations in genes previously linked to embryonic lethality in severe cases, our approach revealed seven novel candidate genes (THSD1, PIGC, UBN1, MYOM1, DNAH14, GALNT14, and FZD6). A founder mutation in one of these genes, THSD1, which has been linked to vascular permeability, accounted for embryonic lethality in three of the study families. Unlike the other six candidate genes, we were able to identify a second mutation in THSD1 in a family with a less severe phenotype consisting of hydrops fetalis and persistent postnatal edema, which provides further support for the proposed link between this gene and embryonic lethality. Conclusions: Our study represents an important step towards the systematic analysis of “embryonic lethal genes” in humans.

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann–like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

Introduction Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of abnormalities that affect structure of the kidneys or other structures of the urinary tract. The majority of CAKUT are asymptomatic and are diagnosed prenatally by ultrasound scanning or found incidentally in postnatal life. CAKUT varies in severity and may lead to life-threatening kidney failure and end-stage kidney disease. Renal agenesis, a severe form of CAKUT, is a congenital absence of one or both kidneys. Bilateral renal agenesis belongs to a group of prenatally lethal renal diseases and is often detected on fetal ultrasound scanning during the investigation of oligohydramnios. Approximately 40% of fetuses with bilateral renal agenesis are stillborn or die a few hours postnatally. Mutations in many renal development genes have been shown to be associated with renal agenesis. Methods Six consanguineous Saudi Arabian families were recruited to study the molecular genetic causes of recurrent miscarriages and lost fetuses due to oligohydramnios, renal agenesis and other congenital anomalies. Whole exome sequencing was employed to underlying detect genetic defects. Results Novel loss of function variants were detected in FRAS1 and FREM2. In FRAS1, a homozygous splice site variant c.9780+2T>C was found in an affected fetus, segregating form each parent. In addition, in three other families both parents were heterozygous for a frameshift variant (c.8981dupT; p.His2995Profs*3) and splice site variants (c.5217+1G>C and c.8098+2T>A), respectively. In FREM2, a homozygous nonsense variant (c.2303C>G; p.Ser768*) was found in an affected fetus, segregating from both parents. In another family, both parents carried a FREM2 heterozygous frameshift variant (c.3969delC; p.Asn1323Lysfs*5). Conclusion We describe consanguineous families with clinical features of antenatal oligohydramnios and bilateral renal agenesis, in whom we have identified novel pathogenic variants in FRAS1 and FREM2. These finding highlights the association between mutations in FRAS1 and FREM2 and antenatal/perinatal death.

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. Methods and Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. Conclusions: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period.

Understanding the impact of SARS-CoV-2 infection on pregnancy outcomes and of pregnancy on COVID-19 outcomes is critical for ensuring proper prenatal and antenatal care. No similar studies have been published in Saudi Arabia. We performed a prospective cohort study of pregnant women with confirmed SARS-CoV-2 infection who presented at King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Kingdom of Saudi Arabia. COVID-19 staging was performed, pregnancy-related complications were assessed, and neonatal infection was evaluated. We enrolled 81 patients (mean age 31.75 years, SD 5.25) of which there were 17 cases in the first trimester, 20 in the second trimester, and 34 in the third trimester. The distribution of COVID-19 severity was 40 patients with Stage A, 36 with Stage B, 4 with Stage C, and 1 with Stage D. Complications were pregnancy loss in 2 patients (one in each first and second trimester) and 1 fetal death after 20 weeks of pregnancy, 7 patients with fetal growth restriction, and 8 with pre-term delivery. We did not observe an unusual frequency of pregnancy-related complications due to SARS-CoV-2 infection in this high-risk obstetric population and there was no evidence of vertical transmission in newborns from women who delivered while positive for the virus.