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

Abstract

De novo variants are increasingly recognized as a common cause of early infantile epileptic encephalopathies. We present a 4-year-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.

Keywords: Autism; Epileptic encephalopathy; Severe global developmental delay.

Figure 1.

(A) The pedigree of the family shows that the parents are first cousins and the phenotypic outcomes for proband and sister. (B) Disease-causing variants reported in GRIA2. Variants from the literature (Salpietro et al. 2019; Zhou et al. 2021; Coombs et al. 2022) and the ClinVar database (Pathogenic/Likely Pathogenic as of 2022-04-28) are plotted on the GRIA2 protein structure (UniProt ID: P42262) and using lollipops (https://github.com/pbnjay/lollipops) v1.5.3 using domain information from PFAM. The full name of the middle domain is “Ligated ion channel L-glutamate- and glycine-binding site.” Variants are shown at their predicted protein position as colored circles reflecting the effect type, with the missense variant reported here shown in black. (C) Sanger sequencing confirmed the de novo variant in GRIA2 (c.1589A > T; p.Lys530Met) in the proband.