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.European Journal of Human Genetics advance online publication, 10 February 2016; doi:10.1038/ejhg.2016.7. © 2016 Macmillan Publishers Limite

PIK3R2/Pik3r2 Activating Mutations Result in Brain Overgrowth and EEG Changes

“…Ventriculomegaly, observed in most human patients, hydrocephalus (present in approximately 50% of human patients) and a rare case of focal cortical dysplasia are also reported components of the syndrome. 2,31 Furthermore, neurologic symptoms associated with this syndrome include mild to severe intellectual disability (100%), oromotor dysfunction (100%), and epilepsy (nearly 50%). 2 In addition, postaxial polydactyly has been reported in 50% of human patients with MPPH (polydactyly was not observed in our mouse model), although rarely in human patients with PIK3R2 mutations.…”

“…The p.G373R is the most common variant out of the 3 reported in human patients with MPPH (p.L401P and p.D557H are the other two). 8,[28][29][30][31] Here, we report that Pik3r2 mutant mice exhibit brain overgrowth and have rare seizures, features overlapping with human patients with MPPH, the vast majority having a germline variant (heterozygote) or rarely somatic mosaicism. 30 Our mouse model provides new insight into the pathogenesis of MPPH and furthermore an opportunity to interrogate potential therapeutics for affected human patients.…”

Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases

“…Somatic point mutation frequency in cancer in both PIK3CA ( 49 ) and PIK3R1 ( 20 , 50 ) is indicated in Figures 2 C,D. Intriguingly, de novo germline and postzygotic, somatic mosaic mutations in similar locations in PIK3CA and PIK3R2 (p85β) also lead to overgrowth and developmental disorder syndromes ( 51 – 56 ), revealing that the same mutant can lead to cancer and/or developmental disorders. There are two hotspot regions in PIK3CA located at the nSH2–helical interface (E542K and E545K) and the C-terminus of the kinase domain (H1047R) involved in membrane binding (Figures 2 B,C).…”

Distribution of disease-causing germline mutations in coiled-coils suggests essential role of their N-terminal region

“…Their complex structure also preserves a groove, providing a room for binding glycerol 28 , which is perturbed by the D557H mutation. The lost direct contact of Asp sidechain with the glycerol, as well as the lack of negative charge positioning the molecule (which is abolished with the positively charged and larger histidine) were proposed to impact binding negatively 29 . PIK3R2 was associated with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus 30 , although the molecular details of the disease were not revealed yet.…”