An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder
| Autor: | Paola Visconti, Magali Jane Rochat, Maria Cristina Scaduto, Leonardo Caporali, Elena Bacchelli, Cinzia Cameli, Marco Seri, Renée C. Duardo, Valerio Carelli, Flavia Palombo, Elena Maestrini, Alessandra Maresca, Fabiola Ceroni, Annio Posar, Pamela Magini, Marta Viggiano, Claudio Fiorini |
|---|---|
| Přispěvatelé: | Cameli C, Viggiano M, Rochat MJ, Maresca A, Caporali L, Fiorini C, Palombo F, Magini P, Duardo RC, Ceroni F, Scaduto MC, Posar A, Seri M, Carelli V, Visconti P, Bacchelli E, Maestrini E. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Proband Male Autism Spectrum Disorder 0302 clinical medicine Gene Regulatory Networks Neural Cell Adhesion Molecules Sequence Deletion Genetics Comparative Genomic Hybridization mtDNA Exons Genomics Phenotype Penetrance Heteroplasmy Autism spectrum disorder 030220 oncology & carcinogenesis Molecular Medicine Original Article Female Adult Mitochondrial DNA Heterozygote DNA Copy Number Variations Biology ASD Deep sequencing 03 medical and health sciences NRXN1 Exome Sequencing medicine Humans Genetic Predisposition to Disease penetrance Gene Genetic Association Studies Gene Expression Profiling Calcium-Binding Proteins rare variants Computational Biology Genetic Variation Infant Cell Biology Original Articles medicine.disease 030104 developmental biology Genome Mitochondrial |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| Popis: | Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%‐30%) presenting a rare large‐effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD‐associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole‐exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion‐transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10−5). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low‐level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large‐effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|