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Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Objectives: To quantify parental acceptance of the COVID-19 vaccine and assess the vaccine hesitancy (VH) for COVID-19 vs. childhood vaccines.Methods: Eight vaccine hesitancy scale (VHS) items, adopted from WHO's Strategic Advisory Group of Immunization (SAGE), were used to assess VH for COVID-19 vaccine vs. routine childhood vaccines. We distributed the online survey to parents with the commence of the national childhood COVID-19 vaccination program in Saudi Arabia.Results: Among 3,167 parents, 47.6% are decided to vaccinate their children against COVID-19. The most common reasons for refusal were inadequate safety information (69%) and worry about side effects (60.6%). Parents have a significantly greater positive attitudes toward children's routine vaccines vs. the COVID-19 vaccine, with higher mean VHS (±SD) = 2.98 ± 0.58 vs. 2.63 ± 0.73, respectively (p-value < 0.001). Parents agreed more that routine childhood vaccines are more essential and effective as compared to the COVID-19 vaccine (Cohen's D: 0.946, and 0.826, consecutively; T-test p-value < 0.00). There is more parental anxiety about serious side effects of the COVID-19 vaccine vs. routine childhood vaccines (Cohen's D = 0.706, p-value < 0.001). Parents who relied on the Ministry of Health information were more predicted (OR = 1.28, p-value = 0.035) to intend to vaccinate as opposed to those who used the WHO website (OR = 0.47, −53%, p-value < 0.001). In a multivariate logistic regression analysis, the factors associated with intention to vaccinate children were parents who received COVID-19 vaccine, older parents, having children aged 12–18, and parents with lower education levels.Conclusions: Significant proportion of parents are hesitant about the COVID-19 vaccine because they are less confident in its effectiveness, safety, and whether it is essential for their children. Relying on the national official healthcare authority's website for the source of information was associated with increased acceptance of childhood COVID-19 vaccination. As parental intention to vaccinate children against COVID-19 is suboptimal, healthcare authorities could boost vaccine uptake by campaigns targeting hesitant parents.

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

ObjectivesThis study aimed to identify COVID-19 vaccine perception, acceptance, confidence, hesitancy, and barriers among healthcare workers (HCW).MethodsAn online national cross-sectional pilot-validated questionnaire was self-administered by HCW in Saudi Arabia, a nation with MERS-CoV experience. The main outcome variable was HCW’s acceptance of COVID-19 vaccine candidates. The associated factors of vaccination acceptance were identified through a logistic regression analysis and the level of anxiety using generalized anxiety disorder 7.ResultOut of 1512 HCWs who completed the study questionnaire—944 (62.4%) women and 568 (37.6%) men—1058 (70%) were willing to receive COVID-19 vaccines. Logistic regression analysis revealed that male HCWs (ORa=1.551, 95% CI: 1.122–2.144), HCWs who believe in vaccine safety (ORa=2.151; 95% CI:1.708–2.708), HCWs who believe that COVID vaccines are the most likely way to stop the pandemic (ORa=1.539; 95% CI: 1.259–1.881), and HCWs who rely on Centers for Disease Control and Prevention website for COVID 19 updates (ORa=1.505, 95% CI: 1.125–2.013) were significantly associated with reporting willingness to be vaccinated. However, HCWs who believed vaccines were rushed without evidence-informed testing were found to be 60% less inclined to accept COVID-19 vaccines (ORa=0.394, 95% CI: 0.298– 0.522).ConclusionMost HCWs are willing to receive COVID-19 vaccines once available; yet, satisfactoriness of COVID-19 vaccination among HCWs is crucial because health professionals’ knowledge and confidence toward vaccines are important determining factors for their own vaccine acceptance and recommendation to their patients.

Background: As the COVID-19 Delta variant has spread across the globe, healthcare workers’ (HCWs) knowledge, worries, and vaccine booster acceptance should be assessed. Methods: Online questionnaires aimed at HCWs in Saudi Arabia were distributed between 9 and 12 August 2021, aiming to evaluate HCWs’ perceptions and worries about the Delta variant as well as their feelings about receiving a booster-vaccine. Results: A total of 1279 HCWs participated, with 51.1% being physicians and 41.7% nurses. 92.5% were aware of the emergence of the Delta variant. Still, only 28.7% were found to have sufficient knowledge of the variant, and their level of worry about it was higher than their level of worry about the Alpha variant (2.32/5 versus 1.79/5). The main information sources cited by the participants were social media (50.5%), while 30.5% used scientific journals. Overall, 55.3% were willing to receive a vaccine booster, while one third would have preferred to receive a new mRNA vaccine specifically developed for the Delta variant. Factors associated with vaccine booster acceptance were receiving both vaccination doses (p = 0.008), believing that the Pfizer-BioNTech BNT162b2 vaccine is effective against variants (p < 0.001), and agreement that mixing/matching vaccines is effective against variants (p < 0.001). Conclusions: A high percentage of HCWs were aware of the Delta variant, but only a small fraction had decent quality of knowledge about it. The participants exhibited high worry levels and showed a modest acceptance of receiving a vaccine booster dose. These results should encourage public health officials to scale up educational efforts to disseminate reliable information about the different variants and provide recommendations about receiving a vaccine booster. Further research on methods to alleviate HCWs’ worries about emerging variants is warranted.

As the Middle East respiratory syndrome coronavirus (MERS-CoV) continues to occur in small outbreaks in Saudi Arabia, we aimed to assess the knowledge, attitudes and intended practices of healthcare workers (HCWs) during the early stage of the COVID-19 pandemic and compare worry levels with previous findings during the MERS-CoV outbreak in 2015. We sent an adapted version of our previously published MERS-CoV questionnaire to the same cohort of HCWs at a tertiary hospital in Saudi Arabia. About 40% of our sample had previous experience with confirmed or suspected MERS-CoV patients, and those had a significantly higher knowledge score (13.16 ± 2.02 vs. 12.58 ± 2.27, P = 0.002) and higher adherence to protective hygienic practices (2.95 ± 0.80 vs. 2.74 ± 0.92, P = 0.003). The knowledge scores on COVID-19 were higher in the current cohort than the previous MERS-CoV outbreak cohort (68% vs. 79.7%, P < 0.001). HCWs from the current cohort who felt greater anxiety from COVID-19 compared to MERS-CoV were less likely to have been exposed to MERS-CoV infected/suspected cases (odds ratio (OR) = 0.646, P = 0.042) and were less likely to have attended the hospital awareness campaign on COVID-19 (OR = 0.654, P = 0.035). We concluded that previous experience with MERS-CoV was associated with increased knowledge and adherence to protective hygienic practices, and reduction of anxiety towards COVID-19.

Background: Healthcare workers' (HCWs') travel-related anxiety needs to be assessed in light of the emergence of SARS-CoV-2 mutations.Methods: An online, cross-sectional questionnaire among HCWs between December 21, 2020 to January 7, 2021. The outcome variables were HCWs' knowledge and awareness of the SARS-CoV-2 B.1.1.7 lineage that was recently reported as the UK variant of concern, and its associated travel worry and Generalized Anxiety Disorder (GAD-7) score.Results: A total of 1,058 HCWs completed the survey; 66.5% were female, 59.0% were nurses. 9.0% indicated they had been previously diagnosed with COVID-19. Regarding the B.1.1.7 lineage, almost all (97.3%) were aware of its emergence, 73.8% were aware that it is more infectious, 78.0% thought it causes more severe disease, and only 50.0% knew that current COVID-19 vaccines are effective in preventing it. Despite this, 66.7% of HCWs were not registered to receive the vaccine. HCWs' most common source of information about the new variant was social media platforms (67.0%), and this subgroup was significantly more worried about traveling. Nurses were more worried than physicians (P = 0.001).Conclusions: Most HCWs were aware of the emergence of the SARS-CoV-2 B.1.1.7 variant and expressed substantial travel worries. Increased worry levels were found among HCWs who used social media as their main source of information, those with lower levels of COVID-19 vaccine uptake, and those with higher GAD-7 scores. The utilization of official social media platforms could improve accurate information dissemination among HCWs regarding the Pandemic's evolving mutations. Targeted vaccine campaigns are warranted to assure HCWs about the efficacy of COVID-19 vaccines toward SARS-CoV-2 variants.