Identity-by-descent analysis of a large Tourette’s syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction

 

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Detalles Bibliográficos
Autores: Ryan, Niamh Margaret, Ormond, Cathal, Chang, Yi-Chieh, Contreras Rojas, Javier, Raventós Vorst, Henriette, Gill, Michael, Heron, Elizabeth A., Mathews, Carol Anne, Corvin, Aiden P.
Formato: artículo original
Fecha de Publicación:2022
Descripción:Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.
País:Kérwá
Institución:Universidad de Costa Rica
Repositorio:Kérwá
Lenguaje:Inglés
OAI Identifier:oai:kerwa.ucr.ac.cr:10669/100239
Acceso en línea:https://hdl.handle.net/10669/100239
https://doi.org/10.1038/s41380-022-01771-9
Palabra clave:Tourette's syndrome
genetics
neuronal development
signal transduction
molecular aetiology
whole-genome sequencing analysis