De novo missense variant in GRIA2 in a patient with global developmental delay, autism spectrum disorder, and epileptic encephalopathy

• Published in: Cold Spring Harbor molecular case studies 2022-06, Vol.8 (4), p.a006172
• Main Authors: Latsko, Maeson S., Koboldt, Daniel C., Franklin, Samuel J., Hickey, Scott E., Williamson, Rachel K., Garner, Shannon, Ostendorf, Adam P., Lee, Kristy, White, Peter, Wilson, Richard K.
• Format: Article
• Language: English
• Subjects: Abnormalities; Autism; Convulsions & seizures; Delay; Encephalopathy; Epilepsy; Gene mapping; Gene sequencing; Genomes; Hereditary diseases; Intellectual disabilities; Neurodevelopmental disorders; Rapid Communication; Seizures; Whole genome sequencing; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a006172

De novo variants are increasingly recognized as a common cause of early infantile epileptic encephalopathies. We present a 4-yr-old male with epileptic encephalopathy characterized by seizures, autism spectrum disorder, and global developmental delay. Whole-genome sequencing of the proband and his unaffected parents revealed a novel de novo missense variant in GRIA2 (c.1589A > T; p.Lys530Met; ENST00000264426.14). Variants in the GRIA2 gene were recently reported to cause an autosomal dominant neurodevelopmental disorder with language impairments and behavioral abnormalities (OMIM; MIM #618917), a condition characterized by intellectual disability and developmental delay in which seizures are a common feature. The de novo variant identified in our patient maps to the edge of a key ligand binding domain of the AMPA receptor and has not been previously reported in gnomAD or other public databases, making it novel. Our findings provided a long-sought diagnosis for this patient and support the link between GRIA2 and a dominant neurodevelopmental disorder.