De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia

Abstract

We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit α. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.

Figure 1

Brain MRI, localization and modeling of PIK3R2-mutated residue. (a-d) Brain MRI of the patient. (a) T1-weighted axial image: bilateral frontoparietal polymicrogyria and incomplete perisylvian opercularization of the right hemisphere (white arrowhead). (b) T2-weighted axial image: thickness and blurring of the cortex-white matter junction in the right temporal cortex (white arrows) with diminished myelination of the underlying white matter and hypoplasia of right cortico-spinal tract. (c) T1-weighted coronal image shows thick cortical infolding with subtle cortical-white matter blurring in the anterior right insula (white arrow) and a cystic lesion in the right frontal operculum (white arrowhead). (d) T1-weighted mid-sagittal image: increased thickness of corpus callosum. Additional brain MRI images are shown in Supplementary Figure S3. (e) Schematic representation of the PIK3R2 protein domains and positions of the variants reported in literature. Thirty-three cases with c.1117G>A (p.(G373R)) de novo and mosaic variants, one case with a de novo c.1126A>G (p.(K376E)) variant and one case with a p.(L401P) de novo variant^{, , ,} were reported beside the c.1669G>C (p.(D557H)) patient described here. SH3, Src homology 3 domain; Rho-GAP, Rho GTPase-activating protein domain; SH2, Src homology 2 domain. (f, g) Context of the c.1669G>C (p.(D557H)) variant. The PIK3CA (uniprot P42336) and PIK3R2 (uniprot O00459) are shown in yellow and cyan ribbon diagrams according to the PDB entry 4l2y model, respectively. (f) Detail view of the interaction showing PIK3R2 D557 and PIK3CA N345 forming an H-bond. (g) Groove of ~311 ų (in green) with a glycerol molecule present in the pdb entry complex showing PIK3R2 D557 residue in direct contact with its surface. A general view of the interaction between PIK3R2 and PIK3CA and positioning of H557 is shown in Supplementary Figure S6.