Dataset Information

Genomic imbalances defining novel intellectual disability associated loci.

ABSTRACT:

Background

High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID).

Results

We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed.

Conclusions

Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

SUBMITTER: Lopes F

PROVIDER: S-EPMC6612161 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Genomic imbalances defining novel intellectual disability associated loci.

Lopes Fátima F Torres Fátima F Soares Gabriela G Barbosa Mafalda M Silva João J Duque Frederico F Rocha Miguel M Sá Joaquim J Oliveira Guiomar G Sá Maria João MJ Temudo Teresa T Sousa Susana S Marques Carla C Lopes Sofia S Gomes Catarina C Barros Gisela G Jorge Arminda A Rocha Felisbela F Martins Cecília C Mesquita Sandra S Loureiro Susana S Cardoso Elisa Maria EM Cálix Maria José MJ Dias Andreia A Martins Cristina C Mota Céu R CR Antunes Diana D Dupont Juliette J Figueiredo Sara S Figueiroa Sónia S Gama-de-Sousa Susana S Cruz Sara S Sampaio Adriana A Eijk Paul P Weiss Marjan M MM Ylstra Bauke B Rendeiro Paula P Tavares Purificação P Reis-Lima Margarida M Pinto-Basto Jorge J Fortuna Ana Maria AM Maciel Patrícia P

Orphanet journal of rare diseases 20190705 1

<h4>Background</h4>High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID).<h4>Result ...[more]

PMID: 31277718

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Project description:MicroRNAs (or miRNAs) are short nucleotide sequences (~17-22 bp long) that play important roles in gene regulation through targeting genes in the 3'untranslated regions (UTRs). Variants located in genomic regions might have different biological consequences in changing gene expression. Exonic variants (e.g., coding variant and 3'UTR variant) are often causative of diseases due to their influence on gene product. Variants harbored in the 3'UTR region where miRNAs perform their targeting function could potentially alter the binding relationships for target pairs, which could relate to disease causation. We gathered miRNA-mRNA targeting pairs from published studies and then employed the database of microRNA Target Site single nucleotide variants (SNVs) (dbMTS) to discover novel SNVs within the selected pairs. We identified a total of 183 SNVs for the 114 pairs of accurate miRNA-mRNA targeting pairs selected. Detailed bioinformatics analysis of the three genes with identified variants that were exclusively located in the 3'UTR section indicated their association with intellectual disability (ID). Our result showed an exceptionally high expression of GPR88 in brain tissues based on GTEx gene expression data, while WNT7A expression data were relatively high in brain tissues when compared to other tissues. Motif analysis for the 3'UTR region of WNT7A showed that five identified variants were well-conserved across three species (human, mouse, and rat); the motif that contains the variant identified in GPR88 is significant at the level of the 3'UTR of the human genome. Studies of pathways, protein-protein interactions, and relations to diseases further suggest potential association with intellectual disability of our discovered SNVs. Our results demonstrated that 3'UTR variants could change target interactions of miRNA-mRNA pairs in the context of their association with ID. We plan to automate the methods through developing a bioinformatics pipeline for identifying novel 3'UTR SNVs harbored by miRNA-targeted genes in the future.

Project description:Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and molecular genetic approaches. A large multigenerational pedigree was ascertained within a Dagestan Genetic Heritage research program in a genetic isolate of indigenous ethnics. Clinical characteristics of the affected members were based on combining diagnoses from regional psychiatric hospitals with our own clinical assessment, using a Russian translation of the structured psychiatric interviews, the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies, based on DSM-IV criteria. Weber/CHLC 9.0 STRs set was used for multipoint parametric linkage analyses (Simwalk2.91). Next, we checked CNVs and LOH (based on Affymetrix SNP 5.0 data) in the linked with ID genomic regions with the aim to identify candidate genes associated with mutations in linked regions. The number of statistically significant (p ? 0.05) suggestive linkage peaks with 1.3 < LOD < 3.0 we detected in a total of 10 genomic regions: 1q41, 2p25.3-p24.2, 3p13-p12.1, 4q13.3, 10p11, 11q23, 12q24.22-q24.31, 17q24.2-q25.1, 21q22.13 and 22q12.3-q13.1. Three significant linkage signals with LOD >3 were obtained at 2p25.3-p24.2 under the dominant model, with a peak at 21 cM flanked by loci D2S2976 and D2S2952; at 12q24.22-q24.31 under the recessive model, with a peak at -120 cM flanked by marker D12S2070 and D12S395 and at 22q12.3 under the dominant model, with a peak at 32 cM flanked by marker D22S683 and D22S445. After a set of genes had been designated as possible candidates in these specific chromosomal regions,we conducted an exploratory search for LOH and CNV based on microarray data to detect structural genomic variants within five ID-linked regions with LOD scores between 2.0 and 3.9. In these selected regions we obtained 173 ROH segments and 98 CN segments. Further analysis of region 2p25.3-p24.2 revealed deletions within genes encoding MYTL, SNTG2 and TPO among five of 21 affected cases at 2p25.3-p24.2. In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500-6,472 kb) and for healthy control 682 kb (531-986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1. Seven of 21 affected pedigree members displayed segmental deletions at 22q12.3 that includes the gene LARGE. Eight affected pedigree members carried ROH segments and 6 CN segments at 10p11.23-p11.21 containing the genes ZEB1, c10orf68 and EPC1. Our linkage and structural genomic variation analyses in a remote highland genetic isolate with aggregation of ID demonstrated that even highly isolated single kindred ID has oligo/polygenic pathogenesis. The results obtained implicate 10 genomic regions linked with ID that contain some of previously reported candidate genes, including HRK, FBXW8, TESC, CDK2AP1 and SBNO1 at 12q24 that were shown in recent studies as associated with brain measures derived from MRI scans.

Dataset Information

Genomic imbalances defining novel intellectual disability associated loci.

Background

Results

Conclusions

Publications

Genomic imbalances defining novel intellectual disability associated loci.

Similar Datasets

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