A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy.

Abstract

Pathogenic variants in glutamate receptor, ionotropic, NMDA-1 (GRIN1) cause an autosomal dominant or recessive neurodevelopmental disorder with global developmental delay, with or without seizures (AD or AR GRIN1-NDD). Here, we describe a novel homozygous canonical splice site variant in GRIN1 in a 12-month-old boy with early infantile epileptic encephalopathy and severe global developmental delay. This represents only the second family with a homozygous predicted-null variant in GRIN1 reported to date. We review the published literature on AR GRIN1-NDD and find that the phenotype in our patient is much more severe than those seen with homozygous missense variants. A similarly severe phenotype of intractable epilepsy and infantile death has only been reported in one other family with a homozygous nonsense variant in GRIN1. We, therefore, propose that biallelic predicted-null variants in GRIN1 can cause a markedly more severe clinical phenotype than AR GRIN1-NDD caused by missense variants.