Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.

PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.

Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes.

Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)-regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage-dependent manner, supporting a loss-of-function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, PDIA6. We recommend screening ATD cases with or without insulin-dependent diabetes for variants in PDIA6.

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

Optimization of water/oil emulsion preparation: Impact of time, speed, and homogenizer type on droplet size and dehydration efficiency.

Due to their distinctive physical and chemical properties, emulsions are widely used in various industries such as pharmaceuticals, cosmetics, food, energy, and oil. Emulsion preparation differs from one application to another due to the effect of multiple parameters that can control droplet size and stability. However, there is a lack of fundamental understanding of the effect of emulsion preparation on its stability and performance. The emulsion preparation protocols can directly affect dehydration efficiency and stability. Herein, we report the influence of preparation conditions on the properties of the formed emulsions; we investigated the effect of mixing time, speed, and mixer type on the synthetic crude oil emulsion's droplet size and dehydration efficiency.

Nurses' Perception Regarding the Quality of Communication between Nurses and Physicians in Emergency Departments in Saudi Arabia: A Cross Sectional Study.

Background: One of the defining characteristics of safe and highly reliable patient care is effective team communication. It is becoming increasingly crucial to improve communication among healthcare team members since social and medical conditions change quickly. Main aim: The present study seeks to assess nurses' perception of the quality of communications between physicians and nurses and associated factors in the emergency departments of selected government hospitals in Saudi Arabia. Methods: A cross-sectional study was carried out in five hospitals in Jazan and three hospitals in Hail City, Saudi Arabia, on a convenience sample of 250 nurses total using self-administered questionnaires. Independent sample t-tests and one-way ANOVA were used for the data analysis. Ethical considerations were adhered to throughout the conduct of the study. Results: The mean score of all domains of nurses' perceptions of the quality of nurse-physician communication in emergency departments was 60.14 out of 90. The highest mean score was observed in the openness subdomain, followed closely by relevance and satisfaction, with mean percentages of 71.65% and 71.60%, respectively. Age, level of education, years of experience, and job position had significant positive correlations with nurses' perceptions of the quality of nurse-physician communication. (p = 0.002, 0.016, 0.022, and 0.020, respectively). Post hoc tests showed that nurses older than 30, those with diplomas, those with more than 10 years' experience, and those in supervisory positions had more positive perceptions of the quality of nurse-physician communication. On the other hand, there was no significant difference in the mean scores of quality of nurse-physician communication with regard to participants' sex, marital status, nationality, and working hours (p > 0.05). Multiple linear regression showed that none of the independent factors affected the nurses' perceptions of the quality of nurse-physician communication in emergency departments (p > 0.05). Conclusions: Overall, the quality of communication between nurses and physicians was not satisfactory. Future research should be meticulously planned, using validated outcome measures, that will capture and reflect the goals of communication among healthcare teams.