Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targetedpanel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.
|Original language||English (US)|
|State||Published - Jun 16 2016|
Bibliographical noteFunding Information:
We thank the patients, their families, and referring providers for their support of our research, and the Macrocephaly-Capillary Malformation (M-CM) Network (https://www.m-cm.net/) for their support as well. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health under award numbers K08NS092898 (to G. Mirzaa), R01NS092772 and R01HL130996 (to W. Dobyns), by the EU Seventh Framework Programme (FP7) under the project DESIRE grant agreement N602531, E-Rare JTC 2011 (to R. Guerrini), and the Wellcome Trust under grant number 102731 (to A. Goriely). G. Mirzaa and W.B. Dobyns had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources have no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication.
© The Author(s), 2016.