Familial occurrence of a 16p13 microdeletion including GRIN2A as a cause of developmental delay and epilepsy with continuous spike and waves during sleep

Gene disruptions, point mutations, and microdeletions of GRIN2A on chromosome 16p13 have been reported in a small number of patients with epilepsy and a highly variable cognitive development (MIM 613971). This gene codes for a subunit of the excitatory neuronal N-methyl-d-aspartate (NMDA) receptor. Here, we report on the clinical phenotype of a family with microdeletion 16p13 involving GRIN2A. The two affected siblings were referred for the first time at the age of 3 and 4 years, respectively, because of developmental delay affecting in particular speech and fine motor skills. Pregnancy and birth were unremarkable, growth measurements and cranial MRI in both children were normal, and there was only minor facial dysmorphism. Both children had already in the initial EEG recordings frequent centrotemporal spikes/sharp-waves with activation and secondary generalization in sleep, corresponding to continuous spike and waves during sleep. Both children received a pulsatile corticoid therapy, which improved the EEG but only lead to limited developmental progress. In both children, clinically no seizures were seen. Intellectual disability with or without epilepsy was reported in several paternal family members. Molecular karyotyping revealed a 773 kb microdeletion in chromosome band 16p13 in both children. The deletion contains 11 genes, including GRIN2A, and overlaps with the deletions in three previously described patients with intellectual disability and seizure disorders of the rolandic region. FISH confirmed that the deletion was inherited from the father. This is the first report of the familial occurrence of a microdeletion 16p13 including GRIN2A. Our observation corroborates the clinical value of molecular karyotyping in patients with apparently monogenic epilepsy associated with variable developmental delay.