Study of candidate genes to Autism Spectrum Disorders

Author(s)

Cintia Marques Ribeiro

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2013-06-07

Examining board members

Maria Rita dos Santos e Passos Bueno; Débora Romeo Bertola; Fernando Kok; Eloisa de Sá Moreira; Andrea Laurato Sertie Santos

• Advisor: Maria Rita dos Santos e Passos Bueno

Abstract

The autism spectrum disorders (ASD) are neuropsychiatric conditions typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviors and interests. Several studies have shown that these disorders have a complex and heterogeneous genetic etiology, which makes difficult to identify the causal factors. Approximately 70% of cases are idiopathic. In order to identify etiological mechanisms associated with ASD, we have used the following strategies: customized a microarray CGH platform that allows detection not only of large CNVs, but also alterations smaller than 10 kbp in exons and UTR regions of potential candidate genes, the comparison between the types of rearrangements detected in syndromic and non-syndromic patients and further, more detailed investigation of a family segregating both autistic disorder and Asperger syndrome. We evaluated 103 nonsyndromic and 18 syndromic patients by the custom-designed array and the detection rate of possibly pathogenic alterations were, respectively, 11.6% and 38.9%. Among these CNVs, 44.4% are smaller than 10 kbp. Therefore, the strategy of using a custom-designed array, enriched with probes targeted to genes potentially involved in the ASD etiology and able to detect both large and small CNVs, seems to be relevant in an attempt to elucidate the largest number of cases and to better understand these disorders. Furthermore, this platform can also be used as a tool to support the clinical diagnosis and genetic counseling with a more affordable cost compared to conventional other or next-generation sequencing. Approximately 33.3% of the observed CNVs affect UTR region, suggesting that mutations in non-coding regions might explain a significant proportion of ASD cases negative for most genomic screenings, which still do not explore adequately these regions. Among nonsyndromic autistic patients we found that most of the genes affected by CNVs are involved in two main biological functions - glutamatergic synapses and axonal guidance, suggesting that nonsyndromic ASD can be caused by dysfunction in different genes of a few common physiological processes. In contrast to our findings in nonsyndromic patients, we detected more than one alteration in a single individual or alterations that involve more than one gene among the syndromic patients, reinforcing the oligogenic model for some cases of ASD. Finally, the data obtained in the study of the family segregating both Asperger syndrome and autistic disorder suggests that the severity of ASD seems to be modulated by the number of hits and possibly by hits in both alleles of the same gene. Our results support the involvement of genes MDGA2, FHIT, HTR2A, SHANK2, GRIA3, ZNF778, PRKCα, CDH15, DIAPH3, GCH1, GRM5, MARK1, SLC17A6, IMMP2L, BZRAP1, SYNGAP1, ANK3, MAP1A, GABRR2 and LAMC3 in ASD etiology and also suggests new candidates: LRRC7, LRRIQ3, CADPS1, NUFIP, SEMA3A, SNAP29, MBD2, GAD2, DGKH and PARD3 (AU)