Thus, in two ASD individuals we have evidence for the possible involvement of more than one locus in the disease, and these findings may support the threshold model of relative contribution in ASD described above (26) and polygenic inheritance in autism. As such, some de novo CNVs may be highly penetrant in causing ASD susceptibility (e.g. disruption of PTCHD1 in Family 1). Conversely, other de novo CNVs (e.g. DPP6 and DPYD deletions) may have more subtle effects, requiring contributions of additional loci (e.g. PTCHD1 missense mutations in the case of Families 9 & 10) for ASD to be phenotypically evident. This scenario may also apply to the ID families with PTCHD1 mutations, although for Family 8 the PTCHD1 missense variant contribution is likely overwhelmed by the phenotypic effect of a whole exon deletion of SLC16A2.
