Developmental Pleiotropy of PTEN in Congenital Hydrocephalus and Autism Spectrum Disorder

Abstract

Abstract INTRODUCTION A population-based study has found that approximately one quarter of individuals diagnosed with congenital hydrocephalus (CH) are also diagnosed with autism spectrum disorder (ASD); however, a common mechanism underlying these seemingly disparate disorders is unknown. We hypothesize that rare, damaging mutations in genes cause a pleiotropic effect responsible for the development of both CH and ASD. METHODS Using WES studies >250 CH patients, we selected 42 DNMs in genes with the greatest probability of loss-of-function (LoF) (pLI > .9), to determine whether there was an enrichment of ASD genes (pLI > .9) found in denovo-db, a national database of ASD DNMs A 2 × 2 contingency table revealed a 2.18-fold enrichment of ASD genes in sporadic CH genes (P-value = . 011). Gene Ontology analysis found >100-fold enrichment of TORC1 signaling (GO: 0031931) as a significantly enriched module (P-value = .000152). We recapitulated the CH phenotype in a genetic mouse model; wherein, Pten, a direct negative regulator of torc1 signaling, is conditionally knocked-out (Pten cKO) in a select subset of NSCs previously associated with an ASD phenotype in mice. Kaplan-Meier survival curves were constructed for Pten cKO and their WT, control littermates. Rapamycin was injected intraperitoneally in Pten cKO and WT mice daily from postnatal (P) days 10 to 22. RESULTS Pten cKO resulted in fully penetrant, fatal hydrocephalus with a median survival of P17.5. WT mice (n = 41) survived significantly longer than Pten cKO mice (n = 10) (P < .0001). Rapamycin rescued the fatal hydrocephalus phenotype (n = 8) by inhibition of mTOR (P < .0001). CONCLUSION PTEN mutations have previously been identified in ASD patients. Here, we present statistical analyses and a mouse model to support our hypothesis that ASD diagnoses in some CH patients may be a neurodevelopmental sequelae of PTEN LoF. These findings suggest that early ASD service interventions may benefit a subset of CH patients who would otherwise be managed solely with surgery.