Case report: A founder UGDH variant associated with developmental epileptic encephalopathy in Saudi Arabia.

Congenital disorders of glycosylation (CDG) are a group of more than 100 rare genetic disorders characterized by impaired glycosylation of proteins and lipids. The clinical presentation of CDG varies tremendously, from single-organ to multi-organ involvement and from prenatal death to a normal adult phenotype. In this case study, we report a large consanguineous family with multiple children suffering from cerebral palsy, seizure, developmental and epileptic encephalopathy, and global developmental delay. Whole-exome sequencing (WES) analysis revealed a homozygous variant in the UDP-glucose dehydrogenase (UGDH) gene (c.950G>A; p.R317Q) which segregates with the familial phenotype with a plausible autosomal recessive mode of inheritance, indicating a potential disease-causing association. The UGDH gene encodes the UDP-glucose dehydrogenase, a key enzyme in the synthesis of specific extracellular matrix constituents (proteoglycans and glycolipids) involved in neural migration and connectivity during early brain development. Many pathogenic mutations of UGDH have been reported in recent literature works. However, the variant identified in this study has been observed only in the Saudi population (13 families) and not in any other ethnic background, suggesting that it may be an ancient founder mutation.

Analysis of chronic kidney disease patients by targeted next-generation sequencing identifies novel variants in kidney-related genes.

Despite the enormous economic and societal burden of chronic kidney disease (CKD), its pathogenesis remains elusive, impeding specific diagnosis and targeted therapy. Herein, we sought to elucidate the genetic causes of end-stage renal disease (ESRD) and identify genetic variants associated with CKD and related traits in Saudi kidney disease patients. We applied a genetic testing approach using a targeted next-generation sequencing gene panel including 102 genes causative or associated with CKD. A total of 1,098 Saudi participants were recruited for the study, including 534 patients with ESRD and 564 healthy controls. The pre-validated NGS panel was utilized to screen for genetic variants, and then, statistical analysis was conducted to test for associations. The NGS panel revealed 7,225 variants in 102 sequenced genes. Cases had a significantly higher number of confirmed pathogenic variants as classified by the ClinVar database than controls (i.e., individuals with at least one allele of a confirmed pathogenic variant that is associated with CKD; 279 (0.52) vs. 258 (0.45); p-value = 0.03). A total of 13 genetic variants were found to be significantly associated with ESRD in PLCE1, CLCN5, ATP6V1B1, LAMB2, INVS, FRAS1, C5orf42, SLC12A3, COL4A6, SLC3A1, RET, WNK1, and BICC1, including four novel variants that were not previously reported in any other population. Furthermore, studies are necessary to validate these associations in a larger sample size and among individuals of different ethnic groups.

Correlation between ABO Blood Group Phenotype and the Risk of COVID-19 Infection and Severity of Disease in a Saudi Arabian Cohort.

BACKGROUND: Disease severity among patients infected with SARS-CoV-2 varies remarkably. Preliminary studies reported that the ABO blood group system confers differential viral susceptibility and disease severity caused by SARS-CoV-2. Thus, differences in ABO blood group phenotypes may partly explain the observed heterogeneity in COVID-19 severity patterns, and could help identify individuals at increased risk. Herein, we explored the association between ABO blood group phenotypes and COVID-19 susceptibility and severity in a Saudi Arabian cohort. METHODS: In this retrospective cohort study, we performed ABO typing on a total of 373 Saudi patients infected with SARS-CoV-2 and conducted association analysis between ABO blood group phenotype and COVID-19 infection severity. We then performed gender-stratified analysis by dividing the participating patients into two groups by gender, and classified them according to age. RESULTS: The frequencies of blood group phenotypes A, B, AB and O were 27.3, 23.6, 5.4 and 43.7%, respectively. We found that blood group phenotype O was associated with a lower risk of testing positive for COVID-19 infection (OR 0.76 95% CI 0.62-0.95, p = 0.0113), while blood group phenotype B was associated with higher odds of testing positive (OR 1.51 95% CI 1.17-1.93, p = 0.0009). However, blood group phenotype B was associated with increased risk in the mild and moderate group but not the severe COVID-19 infection group. Blood group phenotype O was protective in all severity groups. CONCLUSION: Our findings provide evidence that blood group phenotype B is a risk for COVID-19 disease while blood group phenotype O is protective from COVID-19 infection. However, further studies are necessary to validate these associations in a larger sample size and among individuals of different ethnic groups.

Association of KIR gene polymorphisms with COVID-19 disease.

BACKGROUND: Natural killer (NK) cells play an essential role against viruses. NK cells express killer cell immunoglobulin-like receptors (KIRs) which regulate their activity and function. The polymorphisms in KIR haplotypes confer differential viral susceptibility and disease severity caused by infections. We investigated the association between KIR genes and COVID-19 disease severity. METHODS: 424 COVID-19 positive patients were divided according to their disease severity into mild, moderate and severe. KIR genes were genotyped using next generation sequencing (NGS). Association between KIR genes and COVID-19 disease severity was conducted and significant correlations were reported. RESULTS: In the COVID-19 patients, KIR Bx genotype was more common than AA genotype. The Bx genotype was found more frequently in patients with mild disease, while in severe disease the AA genotype was more common than the Bx genotype. The KIR2DS4 gene carried the highest risk for severe COVID-19 infection (OR 8.48, pc= 0.0084) followed by KIR3DL1 (OR 7.61, pc= 0.0192). CONCLUSIONS: Our findings suggest that KIR2DS4 and KIR3DL1 genes carry risk for severe COVID-19 disease.

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

Role of sphingolipid metabolism in neurodegeneration.

Sphingolipids are a class of lipids highly enriched in the central nervous system (CNS), which shows great diversity and complexity, and has been implicated in CNS development and function. Alterations in sphingolipid metabolism have been described in multiple diseases, including those affecting the central nervous system (CNS). In this review, we discuss the role of sphingolipid metabolism in neurodegeneration, evaluating its direct roles in neuron development and health, and also in the induction of neurotoxic activities in CNS-resident astrocytes and microglia in the context of neurologic diseases such as multiple sclerosis and Alzheimer's disease. Finally, we focus on the metabolism of gangliosides and sphingosine-1-phosphate, its contribution to the pathogenesis of neurologic diseases, and its potential as a candidate target for the therapeutic modulation of neurodegeneration.

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.