GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Abstract

Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.

Methods: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.

Results: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.

Conclusions: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Keywords: channelopathy; clustering of missense variants; epileptic encephalopathy; pathogenic GRIN2B mutations; precision medicine.

Figure 1

MRI of patients with malformation of cortical development. MRI scans of patients p.(Ala639Val) (A–D), p.(Ser810Arg) (E–H), p.(Ile655Phe) (I–L), p.(Ala636Val) (M–P), p.(Arg693Ser) (Q–T), p.(Ser810Asn) (U–X), and a normal control (AA-DD) showing T1-weighted mid-sagittal images (first column), T2-weighted axial images through the basal ganglia (second column) and higher lateral ventricles (third column), and T2-weighted coronal images through the hippocampus (fourth column). The mid-sagittal images are normal except for mildly low forehead in several subjects (A, I, U), although several are slightly off the midline. The lower axial images show relatively large and mildly dysplastic basal ganglia compared with normal (asterisks in B, (F, J, N, R and V)). All axial images (middle two rows) show a diffuse irregular gyral pattern with small gyri and limited intracortical microgyri (white arrows on the right side of images that point to the left hemispheres), an appearance intermediate between typical polymicrogyria and the cortical appearance of tubulinopathies. The coronal images show hippocampal dysplasia with thick leaves and open hilus, which varies from severe (D, H, X) to moderate (L, P).

Figure 2

De novo variants in GRIN2B. (A) Clustering of (likely) pathogenic missense variants in GRIN2B. All but one of the (likely) pathogenic missense variants cluster in the ligand-binding or transmembrane domains of GluN2B, which are regions with little to no benign missense variation in the control population. The de novo missense p.(Arg1111His) and the inframe deletion p.(Lys976del) in the CTD were classified as VUS. (B) Location of pathogenic truncating variants in GRIN2B. The recurrent variant c.99dupC, p.(Ser34Glnfs*25) listed in ExAC is part of a homopolymer stretch of seven recurrent C nucleotides suggesting a technical artefact. Variants classified as VUS establish a premature termination codon in the last exon of GRIN2B, including a de novo truncating variant in a control individual p.(Arg1099Alafs*51). Red bars indicate pathogenic/likely pathogenic de novo variants. Blue bars indicate de novo VUS. Grey bars indicate single nucleotide variants (SNV) listed in one ExAC individual each. Black bars indicate SNV seen in more than one ExAC individual. ATD, amino-terminal domain; CTD, carboxy-terminal domain; ExAC, Exome Aggregation Consortium; M1–M4, transmembrane domain; S1, S2, ligand-binding domain; VUS, variants of unknown significance.