Dados do Trabalho

Título

Mutational mechanisms linking GRIN2A to epileptic encephalopathy events during sleep

Introdução

GRIN2A rare coding variants are one of the main genetic factors associated with phenotypes in the epilepsy-aphasia spectrum, such as Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike-waves during sleep (ECSWS). These conditions cause recurrent epileptic seizures and impairment of language skills. Their most distinctive feature are characteristic patterns of abnormal electrical brain activity during slow wave sleep.

Objetivo

We evaluated the divergencies and commonalities between molecular disruptions associated with different mutational mechanisms affecting GRIN2A in patients on the epilepsy-aphasia spectrum.

Métodos

We systematically reviewed all articles published in the last 10 years that reported GRIN2A variants associated with epilepsy-aphasia spectrum disorders. From a total of 11 publications, we selected pathogenic or likely pathogenic missense variants affecting the most important protein domains coded by this gene (i.e. glutamate binding (GB) and pore-forming (PF)) and their flanking regions. Prediction scores from protein damaging effects of 23 variants, reported in a total of 59 patients, and gnomAD populational dataset were used to define protein regions that are conserved against gain and function (GoF) and loss of function (LoF) variation.

Resultados

13 variants were detected in more than one patient, of which 7 were inherited, indicating incomplete penetrance, and 6 were de novo. GB was the most affected protein domain, harboring 15 variants, followed by PF, with 8 variants. The most frequently reported phenotypes were rolandic epilepsy, CSWS and LKS. The GB domain was associated with multiple epileptic encephalopathy phenotypes, while PF was found to be mostly associated with CSWS. 4 GB-region variants were reported among exome and/or genome samples on gnomAD, of which 3 were reported as inherited. From variants with functional validation, 15 were LoF, with all of them affecting GB, with equal rates of de novo and inherited herdability. All 3 GoF variants were associated with the PF domain and reported to be de novo.

Conclusões

The mutational mechanisms acting on GB and PF domains diverge on penetrance, protein activity effects and clinical consequences. Dissecting the molecular consequences of disease-relevant missense variants can lead to precise functional modeling and precision medicine approaches.

Palavras -chave

Sleep
GRIN2A
Epilepsy
Landau Kleffner Syndrome
Epileptic Encephalopathy with Diffuse Continuous Spike-Waves During Slow-Wave Sleep