Gene variants in periventricular nodular heterotopia

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development (MCD) mainly caused by aberrant neuronal migration, and a group of diseases sharing similar pathological manifestations, including the presence of nodular clusters of abnormal neurons in the subependymal region. PVNH is one of major causes that result in genetic epilepsy. Seizures can strike as early as a few days after birth but are more common at 10-20 years old, and among them, generalized tonic-clonic seizures are commonly observed. PVNH is a highly genetically heterogeneous disease associated with various rare single gene variants. However, despite the fact that the FLNA gene is identified to be closely correlated with the presence of PVNH, mutations in other genes were understudied and have not attracted as much attention due to the relatively low morbidity of PVNH. In consequence, an updated spectrum of PVNH-associated risk genes with potentially pathogenic changes that lead to PVNH in human patients is urgently needed. The risk genes that have already been clinically reported for PVNH are summarized here chronologically according to when the first patient was reported, and clinical manifestations of patients with each of these genes are described. Human cerebral organoids as well as animal models are subsequently discussed in this review to reveal alterations in risk gene products and the pathogenesis of PVNH.