Pediatric-onset ataxias often present clinically as developmental
delay and intellectual disability, with prominent cerebellar
atrophy as a key neuroradiographic finding. Here we describe a
new clinically distinguishable recessive syndrome in 12 families
with cerebellar atrophy together with ataxia, coarsened facial
features and intellectual disability, due to truncating mutations
in the sorting nexin gene SNX14, encoding a ubiquitously
expressed modular PX domain–containing sorting factor.
We found SNX14 localized to lysosomes and associated with
phosphatidylinositol (3,5)-bisphosphate, a key component
of late endosomes/lysosomes. Patient-derived cells showed
engorged lysosomes and a slower autophagosome clearance
rate upon autophagy induction by starvation. Zebrafish
morphants for snx14 showed dramatic loss of cerebellar
parenchyma, accumulation of autophagosomes and activation
of apoptosis. Our results characterize a unique ataxia syndrome
due to biallelic SNX14 mutations leading to lysosomeautophagosome
dysfunction.