Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study

Almeida, J.

Café, C.

Coelho, J.

Conceição, I.C.

Correia, C.T.

Duque, F

Gao, K.

Geschwind, D.H.

Lowe, J.K.

Marshall, C.R.

Mouga, S.

Nurnberger, J.I.

Oliveira, B.

Oliveira, G.

Pinto, D.

Roberts, W.

Scherer, S.W.

Sequeira, A.F.

Sousa, I.

Thiruvahindrapuram, B.

Vicente, A.M.

Walker, S.

Molecular Autism

PubMed

BACKGROUND:
Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study.
METHODS:
From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants.
RESULTS:
The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance.
CONCLUSIONS:
We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD

Correia, CT

Conceição, IC

Oliveira, B

Coelho, J

Sousa, I

Sequeira, AF

Almeida, J

Café, C

Mouga, S

Roberts, W

Gao, K

Lowe, JK

Thiruvahindrapuram, B

Walker, S

Marshall, CR

Pinto, D

Geschwind, JI

Scherer, SW

Oliveira, G

Vicente, AM

Name not available

Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders

Repositório Científico do Instituto Nacional de Saúde

CHUC Institutional Repository

Scientific Repository of the National Health Institute Doutor Ricardo Jorge

Catarina T Correia

Inês C Conceição

Bárbara Oliveira

Joana Coelho

Inês Sousa

Ana F Sequeira

Joana Almeida

Cátia Café

Frederico Duque

Susana Mouga

Wendy Roberts

Kun Gao

Jennifer K Lowe

Bhooma Thiruvahindrapuram

Susan Walker

Christian R Marshall

Dalila Pinto

John I Nurnberger

Stephen W Scherer

Daniel H Geschwind

Guiomar Oliveira

Astrid M Vicente

Springer - Publisher Connector

Background: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide
studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance
patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the
annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study.
Methods: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene
duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up
sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing
of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants.
Results: The ANXA1 duplication, overlapping the last four exons and 3’UTR region, had an overall prevalence of 11/
3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no
distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives
carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3’UTR
identified 11 novel changes, but no obvious variants with clinical significance.
Conclusions: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator
of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the
neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.We gratefully acknowledge the children with ASD and their families for their
collaboration. We thank the AGP investigators for sharing data, resources,
and scientific discussions. The AGP study was funded by Autism Speaks
(USA), the Health Research Board (HRB, Ireland; AUT/2006/1, AUT/2006/2,
PD/2006/48), The Medical Research Council (MRC, UK), Genome Canada/
Ontario Genomics Institute and the Hilibrand Foundation (USA). Additional
support for individual groups was provided by the US National Institutes of
Health (NIH Grants: HD055751, HD055782, HD055784, MH52708, MH55284,
MH061009, MH06359, MH066673, MH080647, MH081754, MH66766,
NS026630, NS042165, NS049261), the Canadian Institutes for Health Research
(CIHR), Assistance Publique – Hôpitaux de Paris (France), Autism Speaks UK,
Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche
Forschungsgemeinschaft (Grant: Po 255/17-4) (Germany), EC Sixth FP AUTISM
MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France,
Fondation FondaMental (France), Fondation Orange (France), Fondation pour
la Recherche Médicale (France), Fundação para a Ciência e Tecnologia
(Portugal), the Hospital for Sick Children Foundation and University of
Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian
Ministry of Health (convention 181 of 19 October 2001), the John P Hussman
Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research
and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science
Council, the Centre for Applied Genomics (Canada), the Utah Autism
Foundation (USA), and the Wellcome Trust core award 075491/Z/04 (UK). We
gratefully acknowledge the resources provided by the Autism Genetic
Resource Exchange (AGRE) Consortium and the participating AGRE families.
The Autism Genetic Resource Exchange is a program of Autism Speaks and
is supported, in part, by grant 1U24MH081810 from the National Institute of
Mental Health to Clara M. Lajonchere (PI). Catarina Correia and Inês C.
Conceição are supported by grants SFRH/BPD/64281/2009 and SFRH/BPD/
74739/2010, respectively, from Fundação para a Ciência e Tecnologia.
Ethical approval was obtained from: i) the Ethics Committee at Hospital
Pediátrico de Coimbra (Portugal) for the Portuguese cases not included in
AGP; ii) the Ethics Committee at the Instituto Nacional de Saúde Doutor
Ricardo Jorge (Portugal) for the Portuguese controls; and iii) the Institutional
Review Board at UCLA for the AGRE sample. The control data from OHI,
approved by the Research Ethics Board of the University of Ottawa Heart
Institute; PopGen, approved by the Ethics Committee of the Medical Faculty
of Kiel and by the data protection officer of the University Hospital
Schleswig-Holstein; CHOP, approved by the Children’s Hospital of Philadelphia
Institutional Review Board; and SAGE, approved by the Institutional Review
Board at each contributing institution (COGA, FSCD, and COGEND) are
published and available. The AGP data involves several research centres and has
already been published; the data is available

Correia, Catarina T.

Conceição, Inês C.

Oliveira, Bárbara

Coelho, Joana

Sousa, Inês

Sequeira, Ana F.

Almeida, Joana

Café, Cátia

Duque, Frederico

Mouga, Susana

Roberts, Wendy

Gao, Kun

Lowe, Jennifer K.

Thiruvahindrapuram, Bhooma

Walker, Susan

Marshall, Christian R.

Pinto, Dalila

Nurnberger, John I.

Scherer, Stephen W.

Geschwind, Daniel H.

Oliveira, Guiomar

Vicente, Astrid M.

Estudo Geral

Repositório Institucional dos Hospitais da Universidade de Coimbra

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Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders

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Name not available

Repositório Científico do Instituto Nacional de Saúde

CHUC Institutional Repository

Scientific Repository of the National Health Institute Doutor Ricardo Jorge

Springer - Publisher Connector

Estudo Geral

Springer - Publisher Connector

Repositório Institucional dos Hospitais da Universidade de Coimbra