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 exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children,Toronto, ON, Canada.
authors: Anath C
authors: AC
authors: Lionel
authors: Andrea K
authors: AK
authors: Vaags
authors: Daisuke
authors: D
authors: Sato
authors: Matthew J
authors: MJ
authors: Gazzellone
authors: Elyse B
authors: EB
authors: Mitchell
authors: Hong Yang
authors: HY
authors: Chen
authors: Gregory
authors: G
authors: Costain
authors: Susan
authors: S
authors: Walker
authors: Gerald
authors: G
authors: Egger
authors: Bhooma
authors: B
authors: Thiruvahindrapuram
authors: Daniele
authors: D
authors: Merico
authors: Aparna
authors: A
authors: Prasad
authors: Evdokia
authors: E
authors: Anagnostou
authors: Eric
authors: E
authors: Fombonne
authors: Lonnie
authors: L
authors: Zwaigenbaum
authors: Wendy
authors: W
authors: Roberts
authors: Peter
authors: P
authors: Szatmari
authors: Bridget A
authors: BA
authors: Fernandez
authors: Lyudmila
authors: L
authors: Georgieva
authors: Linda M
authors: LM
authors: Brzustowicz
authors: Katharina
authors: K
authors: Roetzer
authors: Wolfgang
authors: W
authors: Kaschnitz
authors: John B
authors: JB
authors: Vincent
authors: Christian
authors: C
authors: Windpassinger
authors: Christian R
authors: CR
authors: Marshall
authors: Rosario R
authors: RR
authors: Trifiletti
authors: Salman
authors: S
authors: Kirmani
authors: George
authors: G
authors: Kirov
authors: Erwin
authors: E
authors: Petek
authors: Jennelle C
authors: JC
authors: Hodge
authors: Anne S
authors: AS
authors: Bassett
authors: Stephen W
authors: SW
authors: Scherer
mesh_terms: D001321:Autistic Disorder; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules; D012326:RNA Splicing / Q000235:genetics; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism
chemical_list: C577410:ARHGEF9 protein, human; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; C430845:NLGN4X protein, human; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D018079:Receptors, GABA; D018009:Receptors, Glycine; D064067:Rho Guanine Nucleotide Exchange Factors; C073441:gephyrin; C082354:neurexin IIIalpha; C098003:neuroligin 2