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.

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.

The aim of the present case-control observational study was to evaluate the peri-implant clinicoradiographic status among betel-quid chewers and controls. Self-reported betel-quid chewers and controls were included. Participants were categorized into 3 groups: Group-1: Individuals chewing betel-quid with tobacco; Group-2: Individuals chewing betel-quid without tobacco; and Group-3: Controls (individuals not using tobacco in any form). Demographic data was collected using a questionnaire. Periodontal and peri-implant clinicoradiologic parameters (plaque and gingival indices [PI and GI], probing depth [PD] and crestal bone loss/marginal bone loss [CBL/MBL]) were assessed. Clinical attachment loss (AL) around teeth was also assessed. Group comparisons were done using the one-way analysis of variance and Bonferroni Post-hoc adjustment tests. Correlation of periodontal and peri-implant inflammatory parameters with the duration of betel-quid chewing habit and duration of placement in the mouth were assessed using logistic regression analysis. P<0.05 was considered statistically significant. Thirty, 30 and 30 patients were included in groups 1, 2 and 3, respectively. Full-mouth PI (P<0.01), GI (P<0.01), clinical AL (P<0.01), PD (P<0.01) and mesial and distal MBL (P<0.01) were higher in groups 1 and 2 than Group-3. Peri-implant mPI (P<0.01), mGI (P<0.01), PD (P<0.01) and MBL/CBL (P<0.01) were significantly higher in groups 1 and 2 than Group-3 with no significant difference in groups 1 and 2. Betel-quid chewing habit either with or without tobacco is a risk-factor of peri-implant soft-tissue inflammation and CBL.

The use of next-generation sequencing (NGS) has helped in identifying many genes that cause congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT, and its association with autosomal recessively inherited genes is expanding. Highly consanguineous populations can impact the detection of recessively inherited genes. Here, we report two families harboring homozygous missense variants in recently described genes, NPNT and GFRA1. Two consanguineous families with neonatal death due to CAKUT were investigated. Fetal ultrasound of probands identified BRA in the first family and severe renal cystic dysplasia in the second family. Exome sequencing coupled with homozygosity mapping was performed, and Sanger sequencing was used to confirm segregation of alleles in both families. In the first family with BRA, we identified a homozygous missense variant in GFRA1: c.362A>G; p.(Tyr121Cys), which is predicted to damage the protein structure. In the second family with renal cystic dysplasia, we identified a homozygous missense variant in NPNT: c.56C>G; p.(Ala19Gly), which is predicted to disrupt the signal peptide site. We report two Saudi Arabian consanguineous families with CAKUT phenotypes that included renal agenesis caused by missense variants in GFRA1 and NPNT, confirming the role of these two genes in human kidney development.

Fetal exposure to toxic metals is a major public health concern, yet the contribution of intrauterine blood transfusion (IUBT) to this exposure remains unclear. This prospective cohort study assessed mercury, cadmium, lead, and arsenic levels in maternal blood, cord blood, and residual IUBT red blood cell (RBC) units from 90 pregnant women enrolled at King Faisal Specialist Hospital & Research Centre. Metals were detected in nearly all maternal and cord blood samples and in every transfusion bag, with several measurements exceeding established benchmark values. Higher maternal mercury and combined mercury–arsenic levels were suggestively associated with small reductions in personal–social scores (approximately −3% to −5%). Elevated cord mercury, arsenic, and combined mercury–arsenic–cadmium levels were associated with modest decreases in problem-solving performance. Increased mercury and mercury–arsenic concentrations in transfused RBCs were linked to lower gross motor scores. Overall, these patterns indicate a potential contribution of IUBT-related metals to fetal exposure, although effect sizes were small. These preliminary findings highlight the importance of monitoring metal content in transfusion materials and reinforce the need for larger studies to clarify their clinical relevance.

Background: Nephronophthisis (NPHP) is an autosomal recessive genetic disorder that can cause early-onset kidney failure. ANKS6 plays an important role in early kidney development and encodes a protein that interacts with other proteins within the primary cilium. ANKS6 mutations are known to cause nephronophthisis 16 (NPHP-16). Little is known regarding fetal ultrasound imaging and the antenatal diagnosis of fetuses with ANKS6-associated kidney disease. Here, we report the detection of ANKS6 variants in consanguineous families with polycystic kidney antenatally and in the early stages of life. Methods: Three unrelated Saudi Arabian patients (two prenatal patients and one neonate) were investigated. These cases were referred to the hospital due to the presence of echogenic kidneys on antenatal scanning. After clinical and phenotypic evaluation, whole-exome sequencing (WES) was performed on the cord and peripheral blood to identify the molecular genetic causes associated with the echogenic kidney phenotypes. Results: Two homozygous sequence variants were detected in ANKS6. The homozygous missense novel variant ANKS6: c.1159A>C was detected in Families 1 and 2. In the third family, the known homozygous loss-of-function variant ANKS6: c.907+2T>A was detected. Conclusions: We identified homozygous ANKS6 variants in three families presenting with antenatal polycystic kidney disease. The findings provide an expanded clinical presentation of ANKS6 and emphasize the utility of WES in the diagnosis of echogenic kidneys in prenatal settings.