<i>PIK3CA</i>-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

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State: Public
Version: Final published version
Serval ID
serval:BIB_4CC9606A7F29
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
<i>PIK3CA</i>-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.
Journal
JCI insight
Author(s)
Mirzaa G., Timms A.E., Conti V., Boyle E.A., Girisha K.M., Martin B., Kircher M., Olds C., Juusola J., Collins S., Park K., Carter M., Glass I., Krägeloh-Mann I., Chitayat D., Parikh A.S., Bradshaw R., Torti E., Braddock S., Burke L., Ghedia S., Stephan M., Stewart F., Prasad C., Napier M., Saitta S., Straussberg R., Gabbett M., O'Connor B.C., Keegan C.E., Yin L.J., Lai A.H., Martin N., McKinnon M., Addor M.C., Boccuto L., Schwartz C.E., Lanoel A., Conway R.L., Devriendt K., Tatton-Brown K., Pierpont M.E., Painter M., Worgan L., Reggin J., Hennekam R., Tsuchiya K., Pritchard C.C., Aracena M., Gripp K.W., Cordisco M., Van Esch H., Garavelli L., Curry C., Goriely A., Kayserilli H., Shendure J., Graham J., Guerrini R., Dobyns W.B.
ISSN
2379-3708 (Print)
ISSN-L
2379-3708
Publication state
Published
Issued date
16/06/2016
Peer-reviewed
Oui
Volume
1
Number
9
Pages
18p.
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of <i>PIK3CA</i> 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 <i>PIK3CA</i> mutations in 60 individuals. Several other individuals ( <i>n</i> = 12) were identified separately to have mutations in <i>PIK3CA</i> by clinical targeted-panel testing ( <i>n</i> = 6), whole-exome sequencing ( <i>n</i> = 5), or Sanger sequencing ( <i>n</i> = 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 <i>PIK3CA</i> mutations were novel. We also identified constitutional <i>PIK3CA</i> mutations in 10 patients. Our molecular data, combined with review of the literature, show that <i>PIK3CA</i> -related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.
Keywords
Class I Phosphatidylinositol 3-Kinases/genetics, Female, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Malformations of Cortical Development/genetics, Mosaicism, Mutation, Phenotype, Tissue Distribution, Vascular Malformations/genetics
Pubmed
Web of science
Open Access
Yes
Create date
21/02/2017 13:08
Last modification date
20/08/2019 15:01
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