Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11

Abstract

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

Figure 1

Summary of Interstitial Deletions of 7q11.23-q21.1 in Cases with and without Infantile Spasms Deletion mapping of cases 1 to 28 defines a critical region for infantile spasms (IS) spanning part of MAGI2. Quantitative real-time PCR amplimers are indicated below the MAGI2 gene along with the two known transcriptional start sites for the α and β isoforms of the protein. MAGI2 is partially or wholly deleted in 12 cases with IS, and another three with childhood epilepsy (cases 11–25). Cases 1–9 and 27–28 have interstitial deletions that are proximal and distal, respectively, to MAGI2 and have had no diagnosis of epilepsy. Case 10 has a diagnosis of IS but is not deleted for MAGI2. Case 26 is deleted for part of MAGI2 but has not had any diagnosis of epilepsy. Chromosome deletions are represented by bars, below a map of genes from the 7q11.23-q21.11 region. Black bars represent deletions in cases with documented seizures, and white bars represent deletions in cases without documented seizures. Grey bars indicate breakpoints that have not been refined.