scholarly journals The 15q11.2 BP1-BP2 Microdeletion (Burnside–Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 3296 ◽  
Author(s):  
Syed K. Rafi ◽  
Merlin G. Butler
Keyword(s):  
Nervous System ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Developmental Disorder ◽  
Disease Association ◽  
The Other ◽  
Prader Willi Syndrome ◽  
System Disease ◽  
Disease Associations ◽  
Number Variation

The 15q11.2 BP1-BP2 microdeletion (Burnside–Butler) syndrome is emerging as the most frequent pathogenic copy number variation (CNV) in humans associated with neurodevelopmental disorders with changes in brain morphology, behavior, and cognition. In this study, we explored functions and interactions of the four protein-coding genes in this region, namely NIPA1, NIPA2, CYFIP1, and TUBGCP5, and elucidate their role, in solo and in concert, in the causation of neurodevelopmental disorders. First, we investigated the STRING protein-protein interactions encompassing all four genes and ascertained their predicted Gene Ontology (GO) functions, such as biological processes involved in their interactions, pathways and molecular functions. These include magnesium ion transport molecular function, regulation of axonogenesis and axon extension, regulation and production of bone morphogenetic protein and regulation of cellular growth and development. We gathered a list of significantly associated cardinal maladies for each gene from searchable genomic disease websites, namely MalaCards.org: HGMD, OMIM, ClinVar, GTR, Orphanet, DISEASES, Novoseek, and GeneCards.org. Through tabulations of such disease data, we ascertained the cardinal disease association of each gene, as well as their expanded putative disease associations. This enabled further tabulation of disease data to ascertain the role of each gene in the top ten overlapping significant neurodevelopmental disorders among the disease association data sets: (1) Prader–Willi Syndrome (PWS); (2) Angelman Syndrome (AS); (3) 15q11.2 Deletion Syndrome with Attention Deficit Hyperactive Disorder & Learning Disability; (4) Autism Spectrum Disorder (ASD); (5) Schizophrenia; (6) Epilepsy; (7) Down Syndrome; (8) Microcephaly; (9) Developmental Disorder, and (10) Peripheral Nervous System Disease. The cardinal disease associations for each of the four contiguous 15q11.2 BP1-BP2 genes are NIPA1- Spastic Paraplegia 6; NIPA2—Angelman Syndrome and Prader–Willi Syndrome; CYFIP1—Fragile X Syndrome and Autism; TUBGCP5—Prader–Willi Syndrome. The four genes are individually associated with PWS, ASD, schizophrenia, epilepsy, and Down syndrome. Except for TUBGCP5, the other three genes are associated with AS. Unlike the other genes, TUBGCP5 is also not associated with attention deficit hyperactivity disorder and learning disability, developmental disorder, or peripheral nervous system disease. CYFIP1 was the only gene not associated with microcephaly but was the only gene associated with developmental disorders. Collectively, all four genes were associated with up to three-fourths of the ten overlapping neurodevelopmental disorders and are deleted in this most prevalent known pathogenic copy number variation now recognized among humans with these clinical findings.

scholarly journals Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

2020 ◽  
Vol 17 (24) ◽  
pp. 9253
Author(s):  
Natália Oliva-Teles ◽  
Maria Chiara de Stefano ◽  
Louise Gallagher ◽  
Severin Rakic ◽  
Paula Jorge ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Chromosomal Region ◽  
Current Knowledge ◽  
Copy Number Variants ◽  
Inclusion Criteria ◽  
Rare Disorders ◽  
Number Variation ◽  
Malformation Syndromes ◽  
Neuropsychiatric Conditions

Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4–BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers’ cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.

scholarly journals The Performance of Gene Expression Signature-Guided Drug–Disease Association in Different Categories of Drugs and Diseases

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2776
Author(s):  
Xiguang Qi ◽  
Mingzhe Shen ◽  
Peihao Fan ◽  
Xiaojiang Guo ◽  
Tianqi Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Drug Repositioning ◽  
Gene Expression Signature ◽  
Disease Association ◽  
Mtor Signaling Pathway ◽  
Immune System Diseases ◽  
Expression Signature ◽  
Chemotherapy Drugs ◽  
Disease Associations

A gene expression signature (GES) is a group of genes that shows a unique expression profile as a result of perturbations by drugs, genetic modification or diseases on the transcriptional machinery. The comparisons between GES profiles have been used to investigate the relationships between drugs, their targets and diseases with quite a few successful cases reported. Especially in the study of GES-guided drugs–disease associations, researchers believe that if a GES induced by a drug is opposite to a GES induced by a disease, the drug may have potential as a treatment of that disease. In this study, we data-mined the crowd extracted expression of differential signatures (CREEDS) database to evaluate the similarity between GES profiles from drugs and their indicated diseases. Our study aims to explore the application domains of GES-guided drug–disease associations through the analysis of the similarity of GES profiles on known pairs of drug–disease associations, thereby identifying subgroups of drugs/diseases that are suitable for GES-guided drug repositioning approaches. Our results supported our hypothesis that the GES-guided drug–disease association method is better suited for some subgroups or pathways such as drugs and diseases associated with the immune system, diseases of the nervous system, non-chemotherapy drugs or the mTOR signaling pathway.

scholarly journals What a psychiatrist needs to know about copy number variants

2015 ◽  
Vol 21 (3) ◽  
pp. 157-163 ◽  
Author(s):  
George Kirov ◽  
Elliott Rees ◽  
James Walters
Keyword(s):  
Risk Factors ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Early Onset ◽  
Copy Number ◽  
Structural Changes ◽  
Developmental Disorder ◽  
Copy Number Variants ◽  
Clinical Genetics

SummaryCopy number variants (CNVs) are structural changes in chromosomes that result in deletions, duplications, inversions or translocations of large DNA segments. Eleven confirmed CNV loci have been identified as rare but important risk factors in schizophrenia. These CNVs are also associated with other neurodevelopmental disorders and medical/physical comorbidities. Although the penetrance of the CNVs for schizophrenia (the chance that CNV carriers will develop the disorder) is modest, the penetrance of CNVs for any early-onset developmental disorder (e.g. intellectual disability or autism) is much higher. Testing for CNVs is now affordable and being used in clinical genetics and neurodevelopmental disorders clinics. It is possible that testing will be expanded to psychiatric clinics. This article provides a clinically relevant overview of recent CNV findings in schizophrenia and related disorders.

scholarly journals Copy-number variation of housekeeping gene rpl13a in rat strains selected for nervous system excitability

2017 ◽  
Vol 33 ◽  
pp. 11-15 ◽  
Author(s):  
Ruslan Kalendar ◽  
Alexander Belyayev ◽  
Tatiana Zachepilo ◽  
Alexander Vaido ◽  
Dmitry Maidanyuk ◽  
...  
Keyword(s):  
Nervous System ◽  
Copy Number Variation ◽  
Copy Number ◽  
Housekeeping Gene ◽  
Rat Strains ◽  
Number Variation

scholarly journals Male-Biased Autosomal Effect of 16p13.11 Copy Number Variation in Neurodevelopmental Disorders

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e61365 ◽  
Author(s):  
Maria Tropeano ◽  
Joo Wook Ahn ◽  
Richard J. B. Dobson ◽  
Gerome Breen ◽  
James Rucker ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Number Variation

scholarly journals Copy Number Variation of UGT 2B Genes in Indian Families Using Whole Genome Scans

2016 ◽  
Vol 2016 ◽  
pp. 1-7
Author(s):  
Avinash M. Veerappa ◽  
Prakash Padakannaya ◽  
Nallur B. Ramachandra
Keyword(s):  
Copy Number ◽  
Gene Deletion ◽  
Indian Population ◽  
Snp Array ◽  
Copy Number Variations ◽  
Genome Scans ◽  
Genome Wide ◽  
Disease Associations ◽  
Number Variation

Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes.Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip.Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4%) than in UGT2B15 (17.6%). Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding.Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases.

scholarly journals Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

2017 ◽  
Author(s):  
Sofia Stamouli ◽  
Britt-Marie Anderlid ◽  
Charlotte Willfors ◽  
Bhooma Thiruvahindrapuram ◽  
John Wei ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Single Cells ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Rare Cnvs ◽  
Number Variation ◽  
Discordant Twins ◽  
Mz Twins

AbstractHundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. Here, we sought to investigate the contribution of CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on MZ pairs discordant for autism spectrum disorder (ASD) using the PsychChip array. In our collection, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. When analyzing the burden of rare CNVs among pairs concordant and discordant for ASD/NDD in comparison with typically developed (TD) pairs, no differences were found. However, we did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p=0.02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood and, in the majority of MZ twins, do not explain the discordance of NDDs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

scholarly journals Duplications at 19q13.33 in patients with neurodevelopmental disorders

2017 ◽  
Author(s):  
Eduardo Pérez-Palma ◽  
Elmo Saarentaus ◽  
Joris Andrieux ◽  
Marie Ravoet ◽  
Giancarlo V. De Ferrari ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Gene Dosage ◽  
Clinical Databases ◽  
Consensus Region ◽  
Number Variation ◽  
Reference Databases ◽  
Copy Number Changes ◽  
Future Evaluation

AbstractOBJECTIVEAfter recent publication of the first patients with disease associated missense variants in GRIN2D, we evaluate the effect of copy number variation (CNV) overlapping this gene towards the presentation of neurodevelopmental disorders.METHODSWe explored ClinVar (N°CNV = 41,398) and DECIPHER (N°CNV = 30,222) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content and expression with publicly available reference databases.RESULTSWe identified 13 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo and comparable CNVs are not present in control databases. All patients were reported to have neurodevelopmental disorders and dysmorphic features as the most common clinical phenotype (N= 10/13), followed by seizures (N= 6/13) and intellectual disability (N= 5/13). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression and gene dosage sensitivity analysis, we highlight four genes for future evaluation: CARD8, C19orf68, KDELR1 and GRIN2D, which are promising candidates for disease causality. Further, investigation of the literature especially supports GRIN2D as the best candidate gene.CONCLUSIONSOur study presents dup19q13.33 as novel duplication syndrome locus associated with neurodevelopmental disorders. CARD8, C19orf68, KDELR1 and GRIN2D are promising candidates for functional follow up.

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