KIF26A is mutated in the syndrome of congenital hydrocephalus with megacolon

Human disorders of the enteric nervous system (ENS), e.g., Hirschsprung’s disease, are rarely associated with major central nervous system involvement. We describe two families each segregating a different homozygous truncating variant in KIF26A with a unique constellation of severe megacolon that resembles Hirschsprung’s disease but lacks aganglionosis as well as brain malformations that range from severe to mild. The intestinal phenotype bears a striking resemblance to that observed in Kif26a −/− mice where KIF26A deficiency was found to cause abnormal GDNF-Ret signaling resulting in failure to establish normal neuronal networks despite myenteric neuronal hyperplasia. Very recently, a range of brain developmental phenotypes were described in patients and mice with KIF26A deficiency and were found to result from abnormal radial migration and increased apoptosis. Our report, therefore, reveals a recognizable autosomal-recessive human KIF26A deficiency phenotype characterized by severe ENS dysfunction and a range of brain malformations.