Exome-wide analysis identify multiple variations in olfactory receptor genes (OR12D2 and OR5V1) associated with autism spectrum disorder in Saudi females.

Background: Autism Spectrum Disorder (ASD) is a multifactorial, neurodevelopmental disorder, characterized by deficits in communication, restricted and repetitive behaviors. ASD is highly heritable in Saudi Arabia; indecencies of affected individuals are increasing. Objectives: To identify the most significant genes and SNPs associated with the increased risk of ASD in Saudi females to give an insight for early diagnosis. Methods: Pilot case-control study mostly emphasized on the significant SNPs and haplotypes contributing to Saudi females with ASD patients (n = 22) compared to controls (n = 51) without ASD. With the use of allelic association analysis tools, 243,345 SNPs were studied systematically and classified according to their significant association. The significant SNPs and their genes were selected for further investigation for mapping of ASD candidate causal variants and functional impact. Results: In females, five risk SNPs at p ≤ 2.32 × 10-05 was identified in association with autism. The most significant exonic variants at chromosome 6p22.1 with olfactory receptor genes (OR12D2 and OR5V1) clustered with high linkage disequilibrium through haplotyping analysis. Comparison between highly associated genes (56 genes) of male and female autistic patients with female autistic samples revealed that 39 genes are unique biomarkers for Saudi females with ASD. Conclusion: Multiple variations in olfactory receptor genes (OR5V1 and OR12D2) and single variations on SPHK1, PLCL2, AKAP9 and LOC107984893 genes are contributing to ASD in females of Arab origin. Accumulation of these multiple predisposed coding SNPs can increase the possibility of developing ASD in Saudi females.

Study of Single Nucleotide Polymorphisms Associated with Breast Cancer Patients among Arab Ancestries.

The aim of this study is to investigate the single nucleotide polymorphisms (SNPs) associated with breast cancer in our population of Arab patients. We investigated 26 breast cancer patients and an equal number of healthy age- and sex-matched control volunteers. We examined the exome wide microarray-based biomarkers and screened 243,345 SNPs for their possible significant association with our breast cancer patients. Successfully, we identified the most significant (p value ≤9.14 × 10-09) four associated SNPs [SNRK and SNRK-AS1-rs202018563G; BRCA2-rs2227943C; ZNF484-rs199826847C; and DCPS-rs1695739G] among persons with breast cancer versus the healthy controls even after Bonferroni corrections (p value <2.05 × 10-07). Although our patients' numbers were limited, the identified SNPs might shed some light on certain breast cancer-associated functional multigenic variations in Arab patients. We assert on the importance of more extensive large-scale analysis to confirm the candidate biomarkers and possible target genes of breast cancer among Arab ancestries.

Emerging of composition variations of SARS-CoV-2 spike protein and human ACE2 contribute to the level of infection: in silico approaches.

SARS-CoV-2 is causative of pandemic COVID-19. There is a sequence similarity between SARS-CoV-2 and SARS-CoV; however, SARS-CoV-2 RBDs (receptor-binding domain) binds 20-fold strongly with human angiotensin-converting enzyme 2 (hACE2) than SARS-CoV. The study aims to investigate protein-protein interactions (PPI) of hACE2 with SARS-CoV-2 RBD between wild and variants to detect the most influential interaction. Variants of hACE2 were retrieved from NCBI and subjected to determine the most pathogenic nsSNPs. Probability of PPIs determines the binding affinity of hACE2 genetic variants with RBD was investigated. Composition variations at the hACE2 and RBD were processed for PatchDock and refined by FireDock for the PPIs. Twelve nsSNPs were identified as the top pathogenic from SNPs (n = 7489) in hACE2 using eight bioinformatics tools. Eight RBD variants were complexed with 12 nSNPS of hACE2, and the global energy scores (Kcal/mol) were calculated and classified as very weak (-3.93 to -18.43), weak (-18.42 to -32.94), moderate (-32.94 to -47.44), strong (-47.44 to -61.95) and very strong (-61.95 to -76.46) zones. Seven composition variants in the very strong zone [G726R-G476S; R768W-V367F; Y252N-V483A; Y252N-V367F; G726R-V367F; N720D-V367F and N720D-F486L], and three in very weak [P263S-S383C; RBD-H378R; G726R-A348T] are significantly (p < 0.00001) varied for global energy score. Zonation of the five zones was established based on the scores to differentiate the effect of hACE2 and RBD variants on the binding affinity. Moreover, our findings support that the combination of hACE2 and RBD is key players for the risk of infection that should be done by further laboratory studies.Communicated by Ramaswamy H. Sarma.

Exome array identifies functional exonic biomarkers for pediatric dental caries.

BACKGROUND: Pediatric dental caries is common among Arab children, however we are still searching for possible genes and molecular mechanisms that influence caries development. AIM: To identity genetic predispositions of dental caries among Saudi children with high DMFT (Decayed, Missing, and Filled Teeth). DESIGN: This case-control study analysed putative functional exonic-variants (n = 243,345) to study the molecular genetics of pediatric caries with high dmft index, 8.75 ± 4.16 on Arab-ancestry subjects with primary dentition (n = 111; 76 cases, dmft>5 and 35 controls, dmft = 0). RESULTS: Pediatric caries is significantly associated with single nucleotide polymorphisms (SNP) in the GRIN2B-rs4764039C (p-value = 2.03 × 10-08) and CFH-rs1065489G (p-value = 8.26 × 10-08) genes, even after Bonferroni correction. Irregular tooth brushing habits (p = 0.0404) and irregular dental visits (p = 0.0050) are significantly associated with caries. Functional enrichment analysis of significant genes is associated with calcium-activated chloride channel, Staphylococcus aureus infection, and N-linked glycosylation. CONCLUSION: Genetic predispositions are found to be significantly associated with the high prevalence of pediatric caries, which is a disorder of multigene-environment interaction. The significant functional exonic variants identified can be biomarkers for the early diagnosis of pediatric dental caries in Arabs.

Whole-Genome Sequencing Reveals Exonic Variation of ASIC5 Gene Results in Recurrent Pregnancy Loss.

Family trio next-generation sequencing-based variant analysis was done to identify the genomic reason on unexplained recurrent pregnancy loss (RPL). A family (dead fetus and parents) from Saudi Arabia with an earlier history of three unexplained RPLs at the ninth week of pregnancy was included in the study. Whole-genome sequencing (WGS) of a dead fetus and the parents was done to identify the pathogenic variation and confirmed through Sanger sequencing. WGS of dead fetus identifies a novel homozygous exonic variation (NM_017419.3:c.680G>T) in ASIC5 (acid-sensing ion channel subunit family member 5) gene; the parents are heterozygous. Newly designed ARMS PCR followed by direct sequencing confirms the presence of heterozygous in one subject and absence of homozygous novel mutation among randomly selected healthy Saudis. The second family with heterozygous was confirmed with three unexplained RPLs. Pathogenicity analysis of R227I amino acid substitution in ASIC5 protein through molecular docking and interaction analysis revealed that the mutations are highly pathogenic, decrease the stability of the protein, and prevent binding of amiloride, which is an activator to open the acid-sensing ion channel of ASIC5. The identified rare and novel autosomal recessive mutation, c.680G>T:p.R227I (ASIC5Saudi), in two families confirm the ASIC5 gene association with RPL and can be fatal to the fetus.

Functional multigenic variations associated with hodgkin lymphoma.

INTRODUCTION: The current study aimed to describe genotypes associated with Hodgkin lymphoma (HL) in a cohort of Saudi and non-Saudi patients and discuss their possible susceptibility to HL. METHODS: We studied clinical, histopathological, and laboratory findings of HL patients admitted over 12 years duration, at King Fahd University Hospital, KSA. The genomic DNAs of HL patients (n = 61) and normal control subjects (n = 36) were extracted, and genotyping was performed using the Illumina human exome bead chip. Set of HL patients and set of normal controls were included in this study. RESULTS: A total of 35 DNA variants were found to be highly significant with the P-value <9.90 × 10-11 among 243 345 exonic biomarkers and obeying the Hardy-Weinberg equilibrium. Nine, MEGF11-rs150945752 (P-value 1.20 × 10-12 ), CACNA1I- s58055559 (P-value 1.93 × 10-12 ), DECR2-rs146760080 (P-value 2.19 × 10-12 ), STAB1-rs143894786 (P-value 2.45 × 10-12 ), ZNF526-rs144433879 (P-value 2.76 × 10-12 ), CPLANE1-rs200612080 (P-value 3.77 × 10-12 ), DLK1-rs1058009 (P-value 5.95 × 10-12 ), RTN4RL2-rs61745214 (P-value 7.71 × 10-12 ), and PGRMC1-rs145582672 (P-value 8.56 × 10-12 ), exonic variants on chromosomes 15, 22, and 16 were highly associated with HL cases. THE HIGHLY SIGNIFICANT HAPLOTYPES AT CHROMOSOME 3: rs143894786G; rs149982219G with P-value = 3.43 × 10-14 was found to be the risk haplotype for the HL patients. The opposite alleles at chromosome 3: rs143894786A; rs149982219G is protective with P-value = 2.46 × 10-12 . Maximum number of SNPs at the chromosome 19: rs144433879C; rs181265966G; rs201144421C; rs145591797G; rs200560875G; rs77270337G (risk P-value = 2.24 × 10-12 ) and its opposite allele rs144433879A; rs181265966A; rs201144421T; rs145591797A; rs200560875A; rs77270337A (protective P-value = 2.60 × 10-9 ) were found to be associated haplotype with the HL and controls, respectively, in Saudi population. CONCLUSION: Our study concludes that the HL is genetically heterogeneous with multigene causation.

Effects of -3.7α Deletion and Sickle-Cell Trait on Ventilatory and Hemodynamic Responses to Maximum Exercise in Young Saudi Females.

INTRODUCTION: Hemoglobinopathies are common disorders in Saudi Arabia and have an impact on the general health of the affected individuals. The current study aimed to find out the effects of the presence of α 3.7 kb rightward deletion or sickle-cell trait (SCT) on ventilatory and hemodynamic parameters of maximum exercise testing in young Saudi women. METHODS: In a cross-sectional study, 75 randomly selected female students from different colleges were tested for VO2max using a COSMED system for maximum exercise testing. Blood parameters and globin genotyping were determined. RESULTS: Hemoglobin genetic studies revealed 28 of the students had 3.7 α-globin deletion only (-3.7α2/α1α2), five had SCT, and 42 had normal α-globin (α1α2/α1α2 and no HbS) and were considered the control group. Subjects with -3.7α2/α1α2 showed significantly lower VO2max and higher resting systolic blood pressure, while SCT carriers showed no difference in regard to ventilatory parameters, but had higher post-exercise systolic blood pressure than controls. CONCLUSION: It is concluded that individuals with 3.7 α-globin deletion might have lower fitness capacity, as demonstrated by lower VO2max, which might explain the general lower VO2max in the young women of this population. Furthermore, increments in resting systolic and posteexercise systolic blood pressure in 3.7 α-globin deletion and SCT, respectively, might indicate a future risk of cardiovascular diseases and require attention and extensive studies.

Risk Y-haplotypes and pathogenic variants of Arab-ancestry boys with autism by an exome-wide association study.

Autism is heterogeneous multifactorial neurodevelopmental and neuropsychiatric disorder with repetitive and limited behaviors as well as communication deficits. Prevalence of autism in males is predominant than females, but their genetic association is unclear. The study was performed to investigate Y-chromosome haplotypes, significant risk variants and susceptibility genes associated with autistic Saudi young males with autism. Exome genotyping microarray analysis was performed in Saudi young boys with autism (cases, n = 47) and without autism and other genetic or neurodevelopmental disorders (control, n = 43) to identify the functional exonic risk variations among 243,345 exonic variations. The most significant single nucleotide polymorphisms (SNPs) of protein coding associated with autism in Saudi young boys were studied for functional enrichment. Y-chromosome haplotyping analysis of 6 SNPs such as rs1865680, rs2032624, rs2032658, rs2032631, rs9786153 and rs13447352 uncovered the most significant protective (ACGACA p = 2.94 × 10-9) among the controls and the high risk Y-haplotype (GAAGTC p = 6.85 × 10-6) among autistic boys. Exome association study revealed 6 susceptible genes, MCC, AUTS2, VSX1, SETBP1, CNTN3, and PCDH11Y that were known for autistic disorder. The significant predisposed genes with functional variants of Y-chromomere are strongly connected with spermatogenic failure (p = 8.02 × 10-8), azoospermia (p = 6.32 × 10-7), partial chromosome Y deletion (p = 7.66 × 10-6), HDMs demethylate histones pathway (p = 3.55 × 10-4) and immune system diseases (p = 4.11 × 10-3). Y-haplotypes and highly significant pathogenic exonic variants in MCC, AUTS2, VSX1, SETBP1, CNTN3 and PCDH11Y genes are more influential genetic factors for developing autism in boys of Arab origin.

State-of-the-art tools to identify druggable protein ligand of SARS-CoV-2.

INTRODUCTION: The SARS-CoV-2 (previously 2019-nCoV) outbreak in Wuhan, China and other parts of the world affects people and spreads coronavirus disease 2019 (COVID-19) through human-to-human contact, with a mortality rate of > 2%. There are no approved drugs or vaccines yet available against SARS-CoV-2. MATERIAL AND METHODS: State-of-the-art tools based on in-silico methods are a cost-effective initial approach for identifying appropriate ligands against SARS-CoV-2. The present study developed the 3D structure of the envelope and nucleocapsid phosphoprotein of SARS-CoV-2, and molecular docking analysis was done against various ligands. RESULTS: The highest log octanol/water partition coefficient, high number of hydrogen bond donors and acceptors, lowest non-bonded interaction energy between the receptor and the ligand, and high binding affinity were considered for the best ligand for the envelope (mycophenolic acid: log P = 3.00; DG = -10.2567 kcal/mol; pKi = 7.713 µM) and nucleocapsid phosphoprotein (1-[(2,4-dichlorophenyl)methyl]pyrazole-3,5-dicarboxylic acid: log P = 2.901; DG = -12.2112 kcal/mol; pKi = 7.885 µM) of SARS-CoV-2. CONCLUSIONS: The study identifies the most potent compounds against the SARS-CoV-2 envelope and nucleocapsid phosphoprotein through state-of-the-art tools based on an in-silico approach. A combination of these two ligands could be the best option to consider for further detailed studies to develop a drug for treating patients infected with SARS-CoV-2, COVID-19.

State-of-the-art tools unveil potent drug targets amongst clinically approved drugs to inhibit helicase in SARS-CoV-2.

INTRODUCTION: The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating coronavirus disease 2019 (COVID-19). The present state-of-the-art tool-based screening was targeted to identify drug targets among clinically approved drugs by uncovering SARS-CoV-2 helicase inhibitors through molecular docking analysis. MATERIAL AND METHODS: Helicase is a vital viral replication enzyme, which unwinds nucleic acids and separates the double-stranded nucleic acids into single-stranded nucleic acids. Hence, the SARS-CoV-2 helicase protein 3D structure was predicted, validated, and used to screen the druggable targets among clinically approved drugs such as protease inhibitor, nucleoside reverse transcriptase inhibitor, and non-nucleoside reverse transcriptase inhibitors, used to treat HIV infection using molecular docking analysis. RESULTS: Interaction with SARS-CoV-2 helicase, approved drugs, vapreotide (affinity: -12.88; S score: -9.84 kcal/mol), and atazanavir (affinity: -11.28; S score: -9.32 kcal/mol), approved drugs for treating AIDS-related diarrhoea and HIV infection, respectively, are observed with significantly low binding affinity and MOE score or binding free energy. The functional binding pockets of the clinically approved drugs on SARS-CoV-2 helicase protein molecule suggest that vapreotide and atazanavir may interrupt the activities of the SARS-CoV-2 helicase. CONCLUSIONS: The study suggests that vapreotide may be a choice of drug for wet lab studies to inhibit the infection of SARS-CoV-2.

Functional DNA variations associated with Saudi female with low VO2max: a pilot microarray study.

The study aims to explore the genetic predispositions and molecular pathways of low cardiorespiratory fitness (VO2max) in young Saudi females (n = 70). Young females were grouped based on the level of VO2max according to the specification of the physical fitness specialist certification as low VO2max (< 28.9; n = 19) and high VO2max (> 33; n = 14) and genotyped for 243345 putative functional exonic variants. The CYFIP2&FNDC9-rs10037485T, C1R-rs75380747G and TOP2A-rs13695C SNPs on chromosome 5, 12 and 17, respectively were found to be the most significant among young Saudi females with low VO2max (P < 8.01 × 10-05). Linkage disequilibrium (LD) analysis among the significant SNPs (P < 0.001) have revealed risk and protective haplotypes with high degree (p-value < 1.0 × 10-4) of LD. The most significant risk haplotypes with the low VO2max in young Saudi females are: Chromosome 1: LOC112268276-rs10800201G; LOC112268276-rs4657537A; rs4657583T (p-value = 2.00 × 10-04); Chromosome 3: rs978979G; CCDC66-rs7637449A; CCDC66-rs111934125T; FAM208A-rs9835332G (p-value = 5.00 × 10-04) and Chromosome 17: STX2-rs13696C; TNS4-rs1901187C (p-value = 1.00 × 10-04). Functional Enrichment Analysis revealed that the genes with SNPs P < 0.001 have significantly involved in the heart rate (P = 0.00442), body weight (P = 0.00629), breath tests (P = 0.0147), proteolysis (P = 0.00623) and cardiac muscle fiber development (P = 0.0263). In conclusion we could say that the identified genetic predispositions and gene-annotation enrichment in low VO2max in young Saudi females revealed that they are at high risk for developing cardiovascular complications.