A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB) is caused by heterozygous mutation in the GRIA2 gene (138247) on chromosome 4q32.

Neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB) is characterized by impaired intellectual development or developmental delay, behavioral abnormalities including autistic features, and language impairment. Other features include seizures and developmental regression (Salpietro et al., 2019).

Salpietro et al. (2019) reported 25 unrelated patients, ranging from 3 months to 31 years of age, with a neurodevelopmental disorder. The patients were ascertained through collaboration of several research centers who shared data from whole-exome, whole-genome, or targeted sequencing that identified GRIA2 mutations. The phenotype represented a spectrum of neurologic deficits, including global developmental delay, impaired intellectual development with poor or absent speech, and behavioral abnormalities, such as autism spectrum disorder, repetitive behaviors, stereotypic movements including hand-flapping, obsessive-compulsive traits, and hyperactivity. Some patients had normal early development, but then showed regression with impaired social and language skills. About half of patients developed early-onset focal or tonic-clonic seizures, most of which were refractory to treatment. Several patients had head growth deceleration, 4 patients were unable to walk, several had gait abnormalities, incoordination, ataxia, or dystonia, and about half were nonverbal. Brain imaging tended to be normal, although some patients had nonspecific abnormalities, such as cerebral atrophy, cerebellar atrophy, and white matter changes. Two patients died in infancy.

The heterozygous mutations in the GRIA2 gene that were identified in patients with NEDLIB by Salpietro et al. (2019) occurred de novo.

In 25 unrelated patients with NEDLIB, Salpietro et al. (2019) identified de novo heterozygous mutations in the GRIA2 gene (see, e.g., 138247.0001-138247.0006). There were 15 missense, 2 splice site, and 1 nonsense mutation, 1 in-frame deletion, and 2 frameshift variants; mutations occurred throughout the gene. The mutations, which were found by whole-genome, whole-exome, or targeted sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The mutations were predicted to result in a loss of function. In vitro functional expression studies in transfected HEK293T cells showed variable effects of the mutations. Seven of 11 mutations caused a decreased agonist-induced current compared to wildtype, 3 mutations had normal current amplitudes, and 1 resulted in an increase in current amplitude. When coexpressed with GRIA1 (138248), most of the mutant proteins showed a decreased current amplitude compared to wildtype, and some affected rectification. Some mutations reduced the GRIA2 surface expression, suggesting that defects in heteromerization or cell surface trafficking may be another important pathogenic mechanism. Overall, most of the mutations appeared to result in a loss of function. No clear genotype/phenotype correlations emerged, although 2 patients who died in infancy both carried the same variant (A639S; 138247.0005). Salpietro et al. (2019) emphasized the biologic diversity of the tested mutants, and suggested that phenotypic differences may arise from different effects of distinct mutations. The report implicated GRIA2 dysfunction and disruption of glutamatergic synaptic transmission in neurodevelopmental disorders.