Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

A. Piton; J. Gauthier; F. F. Hamdan; R. G. Lafrenière; Y. Yang; E. Henrion; S. Laurent; A. Noreau; P. Thibodeau; L. Karemera; D. Spiegelman; F. Kuku; J. Duguay; L. Destroismaisons; P. Jolivet; M. Côté; K. Lachapelle; O. Diallo; A. Raymond; C. Marineau; N. Champagne; L. Xiong; C. Gaspar; J. B. Rivière; J. Tarabeux; P. Cossette; M. O. Krebs; J. L. Rapoport; A. Addington; L. E. Delisi; L. Mottron; R. Joober; E. Fombonne; P. Drapeau; G. A. Rouleau

doi:10.1038/mp.2010.54

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

A. Piton, J. Gauthier, F. F. Hamdan, R. G. Lafrenière, Y. Yang, E. Henrion, S. Laurent, A. Noreau, P. Thibodeau, L. Karemera, D. Spiegelman, F. Kuku, J. Duguay, L. Destroismaisons, P. Jolivet, M. Côté, K. Lachapelle, O. Diallo, A. Raymond, C. MarineauN. Champagne, L. Xiong, C. Gaspar, J. B. Rivière, J. Tarabeux, P. Cossette, M. O. Krebs, J. L. Rapoport, A. Addington, L. E. Delisi, L. Mottron, R. Joober, E. Fombonne, P. Drapeau, G. A. Rouleau

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Abstract

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n142; 122 males and 20 females) or SCZ (n143; 95 males and 48 females). We identified < 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Original language	English (US)
Pages (from-to)	867-880
Number of pages	14
Journal	Molecular Psychiatry
Volume	16
Issue number	8
DOIs	https://doi.org/10.1038/mp.2010.54
State	Published - Aug 2011
Externally published	Yes

Keywords

X chromosome
autism spectrum disorder
rare variants
schizophrenia
synaptic genes

ASJC Scopus subject areas

Molecular Biology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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10.1038/mp.2010.54

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Piton, A., Gauthier, J., Hamdan, F. F., Lafrenière, R. G., Yang, Y., Henrion, E., Laurent, S., Noreau, A., Thibodeau, P., Karemera, L., Spiegelman, D., Kuku, F., Duguay, J., Destroismaisons, L., Jolivet, P., Côté, M., Lachapelle, K., Diallo, O., Raymond, A., ... Rouleau, G. A. (2011). Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Molecular Psychiatry, 16(8), 867-880. https://doi.org/10.1038/mp.2010.54

Piton, A, Gauthier, J, Hamdan, FF, Lafrenière, RG, Yang, Y, Henrion, E, Laurent, S, Noreau, A, Thibodeau, P, Karemera, L, Spiegelman, D, Kuku, F, Duguay, J, Destroismaisons, L, Jolivet, P, Côté, M, Lachapelle, K, Diallo, O, Raymond, A, Marineau, C, Champagne, N, Xiong, L, Gaspar, C, Rivière, JB, Tarabeux, J, Cossette, P, Krebs, MO, Rapoport, JL, Addington, A, Delisi, LE, Mottron, L, Joober, R, Fombonne, E, Drapeau, P & Rouleau, GA 2011, 'Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia', Molecular Psychiatry, vol. 16, no. 8, pp. 867-880. https://doi.org/10.1038/mp.2010.54

@article{271fef2bb0104f00a8c840dfdceeb586,

title = "Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia",

abstract = "Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n142; 122 males and 20 females) or SCZ (n143; 95 males and 48 females). We identified < 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).",

keywords = "X chromosome, autism spectrum disorder, rare variants, schizophrenia, synaptic genes",

author = "A. Piton and J. Gauthier and Hamdan, {F. F.} and Lafreni{\`e}re, {R. G.} and Y. Yang and E. Henrion and S. Laurent and A. Noreau and P. Thibodeau and L. Karemera and D. Spiegelman and F. Kuku and J. Duguay and L. Destroismaisons and P. Jolivet and M. C{\^o}t{\'e} and K. Lachapelle and O. Diallo and A. Raymond and C. Marineau and N. Champagne and L. Xiong and C. Gaspar and Rivi{\`e}re, {J. B.} and J. Tarabeux and P. Cossette and Krebs, {M. O.} and Rapoport, {J. L.} and A. Addington and Delisi, {L. E.} and L. Mottron and R. Joober and E. Fombonne and P. Drapeau and Rouleau, {G. A.}",

note = "Funding Information: We thank the families involved in our study and the recruitment coordinators (Anne Desjarlais, Caroline Poulin, and Sabrina Diab). We thank Annie Levert, Judith St-Onge, and Isabelle Bachand for performing DNA extraction and paternity and identity testing. We are thankful for the efforts of the members of the McGill University and Genome Quebec Innovation Centre Sequencing (Pierre Lepage, S{\'e}bastien Brunet, and Hao Fan Yam) and Bioinformatic (Louis L{\'e}tour-neau and Louis Dumond Joseph) groups. This work was supported by a grant from Genome Canada and G{\'e}nome Qu{\'e}bec and was cofunded by Universit{\'e} de Montr{\'e}al, for the {\textquoteleft}Synapse-to-disease{\textquoteright} (S2D) project.",

year = "2011",

month = aug,

doi = "10.1038/mp.2010.54",

language = "English (US)",

volume = "16",

pages = "867--880",

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T1 - Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

AU - Piton, A.

AU - Gauthier, J.

AU - Hamdan, F. F.

AU - Lafrenière, R. G.

AU - Yang, Y.

AU - Henrion, E.

AU - Laurent, S.

AU - Noreau, A.

AU - Thibodeau, P.

AU - Karemera, L.

AU - Spiegelman, D.

AU - Kuku, F.

AU - Duguay, J.

AU - Destroismaisons, L.

AU - Jolivet, P.

AU - Côté, M.

AU - Lachapelle, K.

AU - Diallo, O.

AU - Raymond, A.

AU - Marineau, C.

AU - Champagne, N.

AU - Xiong, L.

AU - Gaspar, C.

AU - Rivière, J. B.

AU - Tarabeux, J.

AU - Cossette, P.

AU - Krebs, M. O.

AU - Rapoport, J. L.

AU - Addington, A.

AU - Delisi, L. E.

AU - Mottron, L.

AU - Joober, R.

AU - Fombonne, E.

AU - Drapeau, P.

AU - Rouleau, G. A.

N1 - Funding Information: We thank the families involved in our study and the recruitment coordinators (Anne Desjarlais, Caroline Poulin, and Sabrina Diab). We thank Annie Levert, Judith St-Onge, and Isabelle Bachand for performing DNA extraction and paternity and identity testing. We are thankful for the efforts of the members of the McGill University and Genome Quebec Innovation Centre Sequencing (Pierre Lepage, Sébastien Brunet, and Hao Fan Yam) and Bioinformatic (Louis Létour-neau and Louis Dumond Joseph) groups. This work was supported by a grant from Genome Canada and Génome Québec and was cofunded by Université de Montréal, for the ‘Synapse-to-disease’ (S2D) project.

PY - 2011/8

Y1 - 2011/8

N2 - Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n142; 122 males and 20 females) or SCZ (n143; 95 males and 48 females). We identified < 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

AB - Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n142; 122 males and 20 females) or SCZ (n143; 95 males and 48 females). We identified < 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

KW - X chromosome

KW - autism spectrum disorder

KW - rare variants

KW - schizophrenia

KW - synaptic genes

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Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

Abstract

Keywords

ASJC Scopus subject areas

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