Genetic variation and complex rearrangements in Autism Spectrum Disorders: implications for genetic counseling

Codina i Solà, Marta

Genetic variation and complex rearrangements in Autism Spectrum Disorders: implications for genetic counseling

Document Type

Doctoral thesis
Published Version

Author

Codina i Solà, Marta

Director

Pérez Jurado, Luis Alberto
Cuscó Martí, Ivon

Publication Date

2016-07-14

Pages

307 p.

License

Citation

Codina i Solà, M. Genetic variation and complex rearrangements in Autism Spectrum Disorders: implications for genetic counseling. Universitat Pompeu Fabra; 2016. handle: http://hdl.handle.net/10803/388031

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

The etiology of Autism Spectrum Disorders (ASD) remains unknown for most of the cases, in spite of its strong genetic component. A greater knowledge of its genetic basis would result in many benefits, including specific genetic counseling for families and, eventually, the development of personalized therapeutic strategies. In this thesis, we have applied several recent sequencing technologies and adapted pipelines to its study. We have investigated the role of rare variants and its transcriptional consequences and explored the contribution of complex rearrangements to its missing heritability. In addition, we have studied second-hit susceptibility genetic factors in a group of individuals with Williams-Beuren syndrome, a genomic disorder associated with a mirror phenotype. Finally, we have explored parental knowledge and the effect of genetic counseling in affected families. Our results reveal that both highly penetrant mutations and inherited variants of milder effect contribute to its susceptibility, following monogenic and oligogenic or multifactorial models, respectively. Each of them may contribute to part of the variability and may explain a subset of cases.
Malgrat el fort component genètic dels Trastorns de l’Espectre Autista (TEA), l’etiologia de la majoria de casos es desconeix. Un major coneixement de les seves bases genètiques seria molt beneficiós, ja que permetria un assessorament genètic específic a les famílies i, a la llarga, el desenvolupament d’estratègies terapèutiques personalitzades. En aquesta tesis, s’han aplicat diverses tècniques recents de seqüenciació i estratègies d’anàlisi adaptades. S’ha investigat el paper de variants rares i les seves conseqüències transcripcionals, així com de reordenaments complexos. A més, hem estudiat la presència de variants de susceptibilitat en un grup de persones amb síndrome de Williams, un trastorn genòmic associat a un fenotip oposat. Finalment, hem explorat el coneixement i les opinions en un grup de famílies afectades i, també, l’efecte de l’assessorament genètic. Els resultats obtinguts indiquen que, en el TEA, hi contribueixen tant mutacions altament penetrants, com variants heretades que augmenten lleugerament el risc i poden seguir tant models monogènics com oligogènics. Cada un d’aquests models contribuiria a explicar part de la variabilitat i dels casos

Keywords

Trastorns de l'Espectre Autista (TEA), Seqüenciació d'exoma, Transcriptoma, Assessorament genètic, Variants genètiques, Autism Spectrum Disorders (ASD), Exome Sequencing, Transcriptome, Genetic Counseling, Genetic variants