Our data add to accumulating evidence for numerous individually rare loci in autism. These include FMR1, MECP2, NLGN3, NLGN4 (9), SHANK3 (10), CNTNAP2 (39–41), A2BP1 (41), NRXN1 (4) (also implicated by inherited CNVs in our study, table S2), and now candidate genes such as PCDH10, DIA1 (c3orf58), NHE9, CNTN3, SCN7A, and RNF8, in addition to chromosomal and CNV anomalies (4, 6–8, 26). Whereas genes involved in glutamatergic transmission seem to be important in autism (4), data from our study and others (6, 42) implicate other biological mechanisms as well. Potential disease mechanisms include failures in neuronal cell adhesion molecules such as NLGN3, NLGN4, and NRXN1; PCDH10 and CNTN3, identified as potential candidates here, may have similar roles. Endosomal trafficking and protein turnover is another potential mechanism implicated by NHE9, which itself is localized to endosomes (43). Further, mutations in NHE6 (which encodes a protein highly related to that encoded by NHE9) were found in a series of patients with an Angelman syndrome–like phenotype, with epilepsy and autism-like symptoms in some patients (37). DIA1 (c3orf58) appears to encode a protein localized to the Golgi apparatus (28), and so may also relate to protein trafficking.
