De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.
Jean-Baptiste
JB
Rivière
Ghayda M
GM
Mirzaa
Brian J
BJ
O'Roak
Margaret
M
Beddaoui
Diana
D
Alcantara
Robert L
RL
Conway
Judith
J
St-Onge
Jeremy A
JA
Schwartzentruber
Karen W
KW
Gripp
Sarah M
SM
Nikkel
Thea
T
Worthylake
Christopher T
CT
Sullivan
Thomas R
TR
Ward
Hailly E
HE
Butler
Nancy A
NA
Kramer
Beate
B
Albrecht
Christine M
CM
Armour
Linlea
L
Armstrong
Oana
O
Caluseriu
Cheryl
C
Cytrynbaum
Beth A
BA
Drolet
A Micheil
AM
Innes
Julie L
JL
Lauzon
Angela E
AE
Lin
Grazia M S
GM
Mancini
Wendy S
WS
Meschino
James D
JD
Reggin
Anand K
AK
Saggar
Tally
T
Lerman-Sagie
Gökhan
G
Uyanik
Rosanna
R
Weksberg
Birgit
B
Zirn
Chandree L
CL
Beaulieu
Jacek
J
Majewski
Dennis E
DE
Bulman
Mark
M
O'Driscoll
Jay
J
Shendure
John M
JM
Graham
Kym M
KM
Boycott
William B
WB
Dobyns
D058534:Class I Phosphatidylinositol 3-Kinases; D059472:Exome; D018095:Germ-Line Mutation; D006801:Humans; D006849:Hydrocephalus / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D054220:Malformations of Cortical Development / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D058627:Megalencephaly / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D013577:Syndrome
D019869:Phosphatidylinositol 3-Kinases; C560566:phosphoinositol-3 kinase regulatory subunit 2, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt