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.

Overlapping cortical malformations in patients with pathogenic variants inGRIN1andGRIN2B

“…Of note, the homozygous variants in individual 8 were truncating variants. These are likely to cause complete LOF of GRIN1 , as has been reported in three siblings and one additional individual with a similar clinical course of neonatal epileptic encephalopathy with homozygous truncating variants in GRIN1 9 12. Homozygous truncating variants causing complete absence of the protein might therefore be at the most severe end of clinical and neuropathological features of LOF variants in GRIN1 .…”

“…Homozygous variants have only rarely been reported in GRIN1 . These include four individuals from two different families with homozygous missense variants, developmental delay and movement disorders but without seizures,9 11 and four individuals from two families with homozygous truncating variants with severe neonatal epileptic encephalopathy 9 12. Homozygous variants in GRIN2B have not been reported yet.…”

Compound‐heterozygous GRIN2A null variants associated with severe developmental and epileptic encephalopathy

“…Our report is the first case of autosomal recessive GRIN2A-related disorder and only the third case where a biallelic knockout of a GluN subunit was associated with human disease, with the other cases affecting GRIN1 c.1666C > T, p.(Gln556*) and c.349-1G > C. 6,7 In the previously published GRIN1 families, the knockout phenotype was associated with severe and fatal neonatal epileptic encephalopathy or severe myoclonic epileptic encephalopathy. Similar to our novel GRIN2A family, knockout phenotypes were much more severe than the phenotype F I G U R E 1 Pedigree of a family with two pathogenic GRIN2A null variants.…”

Microcephaly in Neurometabolic Diseases

“…However, autosomal recessive cases of GRIN1- NDD also have been reported (OMIM 617820). Fewer than 100 cases of GRIN1-NDD have been described [ 40 ].…”

“…Gastrointestinal symptoms such as feeding problems are also present. The disorder should be suspected in individuals with typical clinical symptoms and typical MR imaging, including cerebral atrophy, ventriculomegaly, and thinning of the corpus callosum [ 38 , 39 , 40 , 41 ].…”