In silico deleterious prediction of nonsynonymous single nucleotide polymorphisms in Neurexin1 gene for mental disorders

Hendam, Ashraf; Al-Sadek, Ahmed Farouk; Hefny, Hesham A.

doi:10.1504/ijbra.2020.104852

Cited by 3 publications

(2 citation statements)

References 35 publications

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“…We applied the following common a priori filtering criteria in workflow 1 and 2: (i) classified as 'exonic', 'splicing', or 'exonic;splicing'; (ii) not classified as synonymous; (iii) not located within a segmentally duplicated region; (iv) a Combined Annotation Dependent Depletion (CADD) Phred score ≥ 20; (v) a positive Genomic Evolutionary Rate Profiling (GERP) score; (vi) shared by at least two family members affected on the TEGI; (vii) multiple damaging scores according to five in silico programs, including SIFT (Sorting Intolerant from Tolerant), PolyPhen-2 (Polymorphism Phenotyping v2), Mutation Assessor, PROVEAN (Protein Variation Effect Analyzer), and MutationTaster2 [37][38][39][40][41][42][43][44]. Articles commonly assess and present multiple in silico prediction scores to provide context for the significance of the identified variants [19,36,[44][45][46][47]. Finally, we applied family-specific criteria (detailed in Tables S4 and S5).…”

Section: Methodsmentioning

confidence: 99%

Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment

et al. 2023

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Individuals with specific language impairment (SLI) struggle with language acquisition despite average non-verbal intelligence and otherwise typical development. One SLI account focuses on grammar acquisition delay. The current study aimed to detect novel rare genetic variants associated with performance on a grammar assessment, the Test of Early Grammatical Impairment (TEGI), in English-speaking children. The TEGI was selected due to its sensitivity and specificity, consistently high heritability estimates, and its absence from all but one molecular genetic study. We performed whole exome sequencing (WES) in eight families with SLI (n = 74 total) and follow-up Sanger sequencing in additional unrelated probands (n = 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (n = 34) from at least two families under two filtering workflows: (1) novel and (2) previously reported candidate genes. Candidate variants were observed on six new genes (PDHA2, PCDHB3, FURIN, NOL6, IQGAP3, and BAHCC1), and two genes previously reported for overall language ability (GLI3 and FLNB). We specifically suggest PCDHB3, a protocadherin gene, and NOL6 are critical for ribosome synthesis, as they are important targets of SLI investigation. The proposed SLI candidate genes associated with TEGI performance emphasize the utility of precise phenotyping and family-based genetic study.

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Section: Methodsmentioning

confidence: 99%

Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment

et al. 2023

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“…In a previous work (Hendam et al 2020 ), a dataset consists of 38 nsSNPs in Neurexin1α and β forms that have been collected from different studies. Two groups of computational tools for predicting the effects of nsSNPs on protein have been applied.…”

Section: Methodsmentioning

confidence: 99%

Molecular Dynamic Simulation of Neurexin1α Mutations Associated with Mental Disorder

2022

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Neurexin1 gene is essential for formulating synaptic cell adhesion to establish synapses. In a previous work, 38 SNPs in Neurexin1 recoded in mental disorder patients have been collected. Five computational prediction tools have been used to predict the effect of SNPs on protein function and stability. Only four SNPs in Neurexin1α have deleterious prediction results from at least four tools. The current work aims to use molecular dynamic simulation (MD) to study the effects of the four mutations on Neurexin1α both on the whole protein as well as identifying affected domains by mutations. A protein model that consists of five domains out of six domains in the real protein was used; missing residues were added, and model was tested for quality. The MD experiment has last for 1.5 μs where four parameters have been used for studying the whole protein in addition to three more parameters for the domain analysis. The whole protein study has shown that two mutations E427I for Autism and R525C for non-syndromic intellectual disability (NSID) have distinctive behavior across the four used parameters. Domain study has confirmed the previous results where the five domains of R525C have acted differently from wild type (WT), while E427I has acted differently for four domains from wild type. The other two mutations D104H and G379E have three domains that only acted differently from wild type. The fourth domain of all mutations has an obvious distinctive behavior from wild type. Further study of E427I and R525C mutations can lead to better understanding of autism and NSID.

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In silico deleterious prediction of nonsynonymous single nucleotide polymorphisms in Neurexin1 gene for mental disorders

Cited by 3 publications

References 35 publications

Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment

Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment

Molecular Dynamic Simulation of Neurexin1α Mutations Associated with Mental Disorder

In-silico analysis of non-synonymous SNPs of human LDLR gene and their impact on familial hypercholesterolemia

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