De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

被引：528

作者：

Riviere, Jean-Baptiste ^{[1
]}

Mirzaa, Ghayda M. ^{[2
]}

O'Roak, Brian J. ^{[3
]}

Beddaoui, Margaret ^{[4
]}

Alcantara, Diana ^{[5
]}

Conway, Robert L. ^{[6
]}

St-Onge, Judith ^{[1
]}

Schwartzentruber, Jeremy A. ^{[7
]}

Gripp, Karen W. ^{[8
]}

Nikkel, Sarah M. ^{[9
]}

Worthylake, Thea ^{[4
]}

Sullivan, Christopher T. ^{[1
]}

Ward, Thomas R. ^{[1
]}

Butler, Hailly E. ^{[1
]}

Kramer, Nancy A. ^{[10
]}

Albrecht, Beate ^{[11
]}

Armour, Christine M. ^{[12
]}

Armstrong, Linlea ^{[13
]}

Caluseriu, Oana ^{[14
]}

Cytrynbaum, Cheryl ^{[15
]}

Drolet, Beth A. ^{[16
,17
]}

Innes, A. Micheil ^{[14
]}

Lauzon, Julie L. ^{[14
]}

Lin, Angela E. ^{[18
]}

Mancini, Grazia M. S. ^{[19
]}

Meschino, Wendy S. ^{[20
]}

Reggin, James D. ^{[21
,22
]}

Saggar, Anand K. ^{[23
]}

Lerman-Sagie, Tally ^{[24
]}

Uyanik, Goekhan ^{[25
]}

Weksberg, Rosanna ^{[15
]}

Zirn, Birgit ^{[26
]}

Beaulieu, Chandree L. ^{[4
]}

Majewski, Jacek ^{[27
]}

Bulman, Dennis E. ^{[28
]}

O'Driscoll, Mark ^{[5
]}

Shendure, Jay ^{[3
]}

Graham, John M., Jr. ^{[10
]}

Boycott, Kym M. ^{[4
,9
]}

Dobyns, William B. ^{[1
,29
,30
]}

机构：

[1] Seattle Childrens Hosp, Ctr Integrat Brain Res, Seattle, WA USA

[2] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[3] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[4] Univ Ottawa, Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON, Canada

[5] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England

[6] Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA

[7] McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[8] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE USA

[9] Childrens Hosp Eastern Ontario, Div Genet, Ottawa, ON K1H 8L1, Canada

[10] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[11] Univ Hosp Essen, Dept Human Genet, Essen, Germany

[12] Queens Univ, Dept Paediat, Kingston, ON, Canada

[13] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[14] Univ Calgary, Dept Med Genet, Calgary, AB, Canada

[15] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[16] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA

[17] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA

[18] MassGen Hosp Children, Dept Med Genet, Boston, MA USA

[19] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands

[20] N York Gen Hosp, Dept Genet, Toronto, ON, Canada

[21] Providence Sacred Heart Med Ctr, Spokane, WA USA

[22] Childrens Hosp, Spokane, WA USA

[23] Univ London, St Georges Hosp, Dept Clin Genet, London, England

[24] Wolfson Med Ctr, Pediat Neurol Unit, Holon, Israel

[25] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Hamburg, Germany

[26] Univ Goettingen, Dept Neuropediat, Gottingen, Germany

[27] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[28] Univ Ottawa, Ottawa Hosp, Res Inst, Ottawa, ON, Canada

[29] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[30] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 08期

基金：

美国国家卫生研究院; 加拿大健康研究院; 英国医学研究理事会;

关键词：

MACROCEPHALY-CAPILLARY MALFORMATION; KINASE-B-GAMMA; GLUCOSE-HOMEOSTASIS; ACTIVATING MUTATION; INSULIN-RESISTANCE; CORPUS-CALLOSUM; CUTIS MARMORATA; COWDEN-DISEASE; GENE-MUTATIONS; HIGH-FREQUENCY;

D O I：

10.1038/ng.2331

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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(1-5). 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.

引用

页码：934 / +

页数：9

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