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.

Evaluating the General Population of Saudi Arabia for Their Knowledge, Attitudes, and Practices Towards Dementia.

Introduction Dementia, a prevalent neurological condition, has a significant global impact on individuals and communities. Despite affecting approximately 50 million people worldwide, with an expected tripling by 2050, there are currently no widely available disease-modifying treatments. Recent efforts have concentrated on strategies involving legislation, regulations, and population-wide initiatives to address dementia risk, diagnosis, and care. Methods This cross-sectional survey engaged 6123 participants in Saudi Arabia, utilizing a multistage sampling design across provinces and cities. The study aimed to investigate the knowledge, attitudes, and practices of the Saudi Arabian general population regarding dementia. Results Participants displayed diverse opinions on dementia knowledge, with females exhibiting higher rates of knowledge, attitudes, and practices than males. Notably, 97.2% of females were aware of dementia compared to 78% of males. The perception of dementia as a healthcare priority was significantly higher in females (84.1%) than in males (59.6%). Older females (≥65) were identified as the age group most associated with dementia (92.50%) compared to males (71.10%). Conclusion While participants demonstrated excellent knowledge of hearing about dementia, understanding symptoms, and identifying modifiable factors, their knowledge regarding prevention and curability was found to be inadequate. A significant gender association was observed, with females exhibiting higher knowledge, attitudes, and practices than males.

Fibroblast growth factor receptor 2 gene (FGFR2) rs2981582T/C polymorphism and susceptibility to breast cancer in Saudi women.

Fibroblast growth factor receptor 2 is a protein encoded by FGFR2 gene and plays an important role in cellular growth. This study was conducted to investigate a potential association of FGFR2 rs2981582 with breast cancer. DNA was obtained from 137 Formalin-fixed, paraffin-embedded tumors and 98 normal breast tissue samples. Genotypes were carried out with PCR-RFLP. The odds ratio and 95% confidence interval (CI) were used to evaluate the power of the associations. A significant association between FGFR2 rs2981582 C allele and susceptibility to breast cancer was found (p-value < 0.0001, Odds Ratio = 2.3, %95 CI (1.5-3.0). No significant differences in FGFR2 rs2981582 genotypes and alleles distribution among breast patients with different hormonal receptor status (p > 0.05) were detected. However, a significant difference was found in genotypes and alleles distribution in ER+, PR- and HER2 between breast cancer cases and controls. This study showed an association of FGFR2 rs2981582T/C with breast cancer in Saudi women, further large study is required to validate the results.