Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes with a LOD score of 5.8 suggesting a founder effect. Sequencing revealed a common deletion of four codons. However, the damaging mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, knockout mouse embryos electroporated with the mutant human construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on . We extended the genetic analysis of these five -linked families versus five non-linked families by studying and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype.