Activating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.335T>A, p.Ile112Asn) in a child with congenital megalencephaly and macrosomia. Functional characterization of patient cells using a variety of endpoints demonstrates increased phosphatidylinositol-3-kinase (PI3K) activity. The mutation lies in a linker region adjacent to the p85 (PIK3R2) binding domain of the p110α (PIK3CA) catalytic subunit of PI3K. We show that altered stoichiometry within the p85-p110 complex likely underlies the hyperactive PI3K-AKT-mTOR signaling in this instance. Our findings expand upon the recently proposed "PIK3CA-related overgrowth spectrum" associated with PIKC3A mutations and PI3K hyperactivation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns.
Bibliographical noteFunding Information:
Cancer Research UK (CR-UK); Medical Research Council (UK); CR-UK; US National Institutes of Health under NINDS (grants NS058721 and K08NS092898). We are grateful to the family for their enthusiastic participation. The mutation has been submitted to the ClinVar database (http://www. ncbi.nlm.nih.gov/clinvar/). Disclosure statement: The authors declare no conflict of interest.
© 2016 Wiley Periodicals, Inc.