Cadherins Matters to Autism Spectrum Disorders: Which Ones?

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with a known strong genetic component. Genomic analysis have shown that de novo and rare loss-of function mutations are important for the etiology of ASD and oligogenic/multifactorial models is expected to be associated with most of the cases. It has also been shown that disruption of genes functionally important for neuronal cytoskeletal and synaptogenesis contributes to the phenotype, but one currently challenge is to identify which are the variants with clinical effect.

Objectives: Identify novel ASD loci or to confirm previous CNVs hits.

Methods: CMA analysis was performed in 121 ASD cases (105 cases using an aCGH 180K platform that was previously customized and validated in our lab, and 16 cases using different CMA platforms). All CNVs detected were characterized by size, type, population frequency and gene content. Common polymorphisms (CNVs occurring in more than 1% of the population) or without genes were excluded from further analysis. International Standard Cytogenomic Array (ISCA) and the American College of Medical Genetic (ACMG) standards were taken into account to classify the remaining CNVs as pathogenic, benign, or variant of uncertain clinical significance (VOUS). Finally, our findings were validated in a cohort of 1,029 Brazilian patients with neurodevelopment disorders

Results: CNV analysis in a Brazilian cohort of 121 patients by chromosomal microarray analysis (CMA) revealed 31 potentially pathogenic CNVs. Of these, 26 contained 27 ASD candidate genes and 15 CNVs contained genes not yet described in ASD patients. Two out of these 31 CNVs embraces genes of the cadherin family (CDH11, CDH8and CDH13). Screening of a Brazilian cohort composed by 1,029 patients with neurodevelopmental disorders revealed one CNV embracing CDH13, TRIM16 and PTPNR2genes, thus reinforcing the association of CDH13with neurodevelopmental disruption. CDH11and CDH8have been pointed out as possible ASD candidate genes and are listed in SFARI database, but with minimum evidence (score 4; http://sfari.org), however, CDH13, which plays an important role in axonal pathfinding and synaptogenesis is not yet included in this database neither suggested as a good ASD candidate.

Conclusions: Our findings suggest that disruption of these cadherin genes may represent a predisposing hit in ASD and CDH13 should be included as a novel ASD candidate gene.

The Project was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP/ CEPID, Conselho Nacional de Desenvolvimento Cientifico e Tecnológico - CNPq and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES