Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.

To identify the underlying genetic cause of autism spectrum disorder (ASD), we performed whole-exome sequencing in 10 unrelated Thai patients with ASD. We identified a novel heterozygous missense variant (c.425C>G, p.Pro142Arg) in the Engrailed 2 (EN2) gene in two patients. The G variant has never been reported in public databases and was absent in 100 Thai patients with ASD and 435 Thai controls. A case-control study showed that the G allele of c.425C>G was significantly associated with ASD (Fisher's exact test, P=0.0359). In addition, the new variant was predicted to be possibly damaging to the EN2 protein by the PolyPhen-2 and FATHMM bioinformatic programs. Our findings suggest that the arginine variant of the EN2 protein may play an important role in the pathology of ASD. Therefore, EN2 protein functional studies should be carried out to determine whether the novel variant has an effect on protein expression.