Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures

Anath C. Lionel; Andrea K. Vaags; Daisuke Sato; Matthew J. Gazzellone; Elyse B. Mitchell; Hong Yang Chen; Gregory Costain; Susan Walker; Gerald Egger; Bhooma Thiruvahindrapuram; Daniele Merico; Aparna Prasad; Evdokia Anagnostou; Eric Fombonne; Lonnie Zwaigenbaum; Wendy Roberts; Peter Szatmari; Bridget A. Fernandez; Lyudmila Georgieva; Linda M. Brzustowicz; Katharina Roetzer; Wolfgang Kaschnitz; John B. Vincent; Christian Windpassinger; Christian R. Marshall; Rosario R. Trifiletti; Salman Kirmani; George Kirov; Erwin Petek; Jennelle C. Hodge; Anne S. Bassett; Stephen W. Scherer

doi:10.1093/hmg/ddt056

Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures

Anath C. Lionel, Andrea K. Vaags, Daisuke Sato, Matthew J. Gazzellone, Elyse B. Mitchell, Hong Yang Chen, Gregory Costain, Susan Walker, Gerald Egger, Bhooma Thiruvahindrapuram, Daniele Merico, Aparna Prasad, Evdokia Anagnostou, Eric Fombonne, Lonnie Zwaigenbaum, Wendy Roberts, Peter Szatmari, Bridget A. Fernandez, Lyudmila Georgieva, Linda M. BrzustowiczKatharina Roetzer, Wolfgang Kaschnitz, John B. Vincent, Christian Windpassinger, Christian R. Marshall, Rosario R. Trifiletti, Salman Kirmani, George Kirov, Erwin Petek, Jennelle C. Hodge, Anne S. Bassett, Stephen W. Scherer

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Abstract

The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses.

Original language	English
Pages (from-to)	2055-2066
Number of pages	12
Journal	Human Molecular Genetics
Volume	22
Issue number	10
DOIs	https://doi.org/10.1093/hmg/ddt056
Publication status	Published - May 2013
Externally published	Yes

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Lionel, A. C., Vaags, A. K., Sato, D., Gazzellone, M. J., Mitchell, E. B., Chen, H. Y., Costain, G., Walker, S., Egger, G., Thiruvahindrapuram, B., Merico, D., Prasad, A., Anagnostou, E., Fombonne, E., Zwaigenbaum, L., Roberts, W., Szatmari, P., Fernandez, B. A., Georgieva, L., ... Scherer, S. W. (2013). Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Human Molecular Genetics, 22(10), 2055-2066. https://doi.org/10.1093/hmg/ddt056

@article{34e9a42d7f494a8387111c84c6a904ab,

title = "Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures",

abstract = "The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses.",

author = "Lionel, {Anath C.} and Vaags, {Andrea K.} and Daisuke Sato and Gazzellone, {Matthew J.} and Mitchell, {Elyse B.} and Chen, {Hong Yang} and Gregory Costain and Susan Walker and Gerald Egger and Bhooma Thiruvahindrapuram and Daniele Merico and Aparna Prasad and Evdokia Anagnostou and Eric Fombonne and Lonnie Zwaigenbaum and Wendy Roberts and Peter Szatmari and Fernandez, {Bridget A.} and Lyudmila Georgieva and Brzustowicz, {Linda M.} and Katharina Roetzer and Wolfgang Kaschnitz and Vincent, {John B.} and Christian Windpassinger and Marshall, {Christian R.} and Trifiletti, {Rosario R.} and Salman Kirmani and George Kirov and Erwin Petek and Hodge, {Jennelle C.} and Bassett, {Anne S.} and Scherer, {Stephen W.}",

note = "Funding Information: A.S.B. holds the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders and received funding support from CIHR grants MOP-89066 and MOP-111238. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. Funding Information: This work was supported by grants from NeuroDevNet, the University of Toronto McLaughlin Centre, Genome Canada and the Ontario Genomics Institute, the Canadian Institutes for Health Research (CIHR), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the Government of Ontario, Autism Speaks, The Hospital for Sick Children Foundation and {\"O}NB Jubil{\"a}umsfonds (Project Number:13226). The control data sets were obtained, along with permission for use, from the database of Genotype and Phenotype database (dbGaP) found at http://www.ncbi.nlm. nih.gov/gap through accession numbers phs000143.v1.p1 (Starr County Study), phs000091.v2.p1 (GENEVA NHS/ HPFS study) and phs000169.v1.p1 (HABC study). A.C.L. holds a NeuroDevNet doctoral fellowship. A.P. was supported by a fellowship from the CIHR Autism Training Program.",

year = "2013",

month = may,

doi = "10.1093/hmg/ddt056",

language = "English",

volume = "22",

pages = "2055--2066",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "10",

}

Lionel, AC, Vaags, AK, Sato, D, Gazzellone, MJ, Mitchell, EB, Chen, HY, Costain, G, Walker, S, Egger, G, Thiruvahindrapuram, B, Merico, D, Prasad, A, Anagnostou, E, Fombonne, E, Zwaigenbaum, L, Roberts, W, Szatmari, P, Fernandez, BA, Georgieva, L, Brzustowicz, LM, Roetzer, K, Kaschnitz, W, Vincent, JB, Windpassinger, C, Marshall, CR, Trifiletti, RR, Kirmani, S, Kirov, G, Petek, E, Hodge, JC, Bassett, AS & Scherer, SW 2013, 'Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures', Human Molecular Genetics, vol. 22, no. 10, pp. 2055-2066. https://doi.org/10.1093/hmg/ddt056

TY - JOUR

T1 - Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures

AU - Lionel, Anath C.

AU - Vaags, Andrea K.

AU - Sato, Daisuke

AU - Gazzellone, Matthew J.

AU - Mitchell, Elyse B.

AU - Chen, Hong Yang

AU - Costain, Gregory

AU - Walker, Susan

AU - Egger, Gerald

AU - Thiruvahindrapuram, Bhooma

AU - Merico, Daniele

AU - Prasad, Aparna

AU - Anagnostou, Evdokia

AU - Fombonne, Eric

AU - Zwaigenbaum, Lonnie

AU - Roberts, Wendy

AU - Szatmari, Peter

AU - Fernandez, Bridget A.

AU - Georgieva, Lyudmila

AU - Brzustowicz, Linda M.

AU - Roetzer, Katharina

AU - Kaschnitz, Wolfgang

AU - Vincent, John B.

AU - Windpassinger, Christian

AU - Marshall, Christian R.

AU - Trifiletti, Rosario R.

AU - Kirmani, Salman

AU - Kirov, George

AU - Petek, Erwin

AU - Hodge, Jennelle C.

AU - Bassett, Anne S.

AU - Scherer, Stephen W.

N1 - Funding Information: A.S.B. holds the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders and received funding support from CIHR grants MOP-89066 and MOP-111238. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. Funding Information: This work was supported by grants from NeuroDevNet, the University of Toronto McLaughlin Centre, Genome Canada and the Ontario Genomics Institute, the Canadian Institutes for Health Research (CIHR), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the Government of Ontario, Autism Speaks, The Hospital for Sick Children Foundation and ÖNB Jubiläumsfonds (Project Number:13226). The control data sets were obtained, along with permission for use, from the database of Genotype and Phenotype database (dbGaP) found at http://www.ncbi.nlm. nih.gov/gap through accession numbers phs000143.v1.p1 (Starr County Study), phs000091.v2.p1 (GENEVA NHS/ HPFS study) and phs000169.v1.p1 (HABC study). A.C.L. holds a NeuroDevNet doctoral fellowship. A.P. was supported by a fellowship from the CIHR Autism Training Program.

PY - 2013/5

Y1 - 2013/5

N2 - The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses.

AB - The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses.

UR - http://www.scopus.com/inward/record.url?scp=84877010942&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddt056

DO - 10.1093/hmg/ddt056

M3 - Article

C2 - 23393157

AN - SCOPUS:84877010942

SN - 0964-6906

VL - 22

SP - 2055

EP - 2066

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 10

ER -

Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures

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