All 11 of the upstream deletions as well as the three PTCHD1 deletions (Families 1 and 2) disrupt conserved (and putative regulatory) sequences and/or exons of these ncRNAs (see Fig. 1). These deletions were not inherited by a subset of the affected family members; also, the missense variants do not segregate with disease in two families (Families 6 & 7) (Fig. 2). These findings are similar to other previously reported, major affect ASD loci such as 16p11.2 (25) and are also consistent with the complex, non-Mendelian inheritance believed to control the etiology of autism. As discussed in a recently proposed threshold model of relative contribution in ASD (26), it is anticipated that multiple common and rare variants may act in concert to generate the phenotype. For instance, under this model, some de novo CNVs may be solely sufficient to cause ASD. Conversely, other de novo CNVs may have weaker effects, requiring contributions from additional loci (for example additional risk haplotypes, or other CNVs), or environmental risk factors, for the burden of contributory factors to cross a risk threshold and result
