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A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy
Author(s) -
Blakes Alexander J. M.,
English Joel,
Banka Siddharth,
Basu Helen
Publication year - 2022
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62528
Subject(s) - missense mutation , phenotype , epilepsy , genetics , encephalopathy , biology , endocrinology , medicine , gene , neuroscience
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.