Further analysis of NHE9 demonstrated deleterious sequence variants associated with similiar autistic phenotypes in patients whose parents were not related. Because the pro-band AU-3101 with the deletion juxtaposed to NHE9 showed autism as well as epilepsy, we sequenced NHE9 in other patients with autism and epilepsy. A heterozygous CGA to TGA transition, changing arginine 423 residue to a stop codon, was found, and it creates a predicted protein truncation in the final extracellular loop of this multispanning transmembrane protein (Fig. 4, A to C). This nonsense change occurs within two amino acids of a similar nonsense mutation in Nhe1 that causes slow-wave epilepsy in mice (36) (Fig. 4B). The swe mouse mutation results in a gene dosage-dependent reduction of protein levels and loss of function in brain (36). A similar nonsense mutation in the final extracellular loop has recently been found in the related NHE6 gene in a patient with an Angelman-like syndrome, which involves both autism symptoms and epilepsy (37). The NHE9 nonsense change here is carried by two male siblings with autistic disorder as well as their mother,
