PMC

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.

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).