Human Gene Module / Chromosome 14 / GPHN

GPHNGephyrin

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 10
Rare Variants / Common Variants
16 / 0
Aliases
GPHN, GEPH,  GPH,  GPHRYN,  HKPX1
Associated Syndromes
-
Chromosome Band
14q23.3
Associated Disorders
ID
Relevance to Autism

A de novo deletion involving the GPHN gene was identified in an ASD case from a simplex family (Prasad et al., 2012). Screening of 8775 cases with ASD, schizophrenia, or epilepsy and 27,019 controls for GPHN deletions determined that experimentally validated deletions in GPHN were significantly greater in cases than in controls (6/8,775 vs. 3/27,019; Fisher's exact two-sided P=0.009); three of the cases with GPHN deletions in this study were diagnosed with ASD (Lionel et al., 2013).

Molecular Function

This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GPHN (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
2 Support Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures Lionel AC , et al. (2013) Yes ID
3 Support Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders Nava C , et al. (2013) Yes ID
4 Recent Recommendation Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy Dejanovic B , et al. (2014) No -
5 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families Egger G , et al. (2014) Yes -
6 Support Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy Dejanovic B , et al. (2015) No -
7 Support Forebrain-specific loss of synaptic GABAA receptors results in altered neuronal excitability and synaptic plasticity in mice O'Sullivan GA , et al. (2016) No -
8 Support Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies Egl P , et al. (2016) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Chan AJS et al. (2022) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 28356794 Egl P , et al. (2016)
- - copy_number_loss De novo - - 24643514 Egger G , et al. (2014)
- - copy_number_loss De novo - Simplex 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Simplex 23393157 Lionel AC , et al. (2013)
- - copy_number_loss Unknown - Simplex 23393157 Lionel AC , et al. (2013)
- - copy_number_loss Familial Paternal Unknown 23632794 Nava C , et al. (2013)
c.100C>T p.Arg34Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.752G>A p.Arg251His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1685A>G p.Glu562Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Paternal Simplex 23393157 Lionel AC , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 24561070 Dejanovic B , et al. (2014)
c.1484A>G p.Glu495Gly missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1620del p.Asn541MetfsTer4 frameshift_variant Unknown - - 36309498 Chan AJS et al. (2022)
- - copy_number_loss Familial Maternal Multi-generational 23393157 Lionel AC , et al. (2013)
c.1124G>A p.Gly375Asp missense_variant De novo - Simplex 26613940 Dejanovic B , et al. (2015)
- - copy_number_loss Familial Paternal Multi-generational 24561070 Dejanovic B , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Screening of 8775 cases with ASD, schizophrenia, or epilepsy and 27,019 controls for GPHN deletions determined that experimentally validated deletions in GPHN were significantly greater in cases than in controls (6/8,775 vs. 3/27,019; Fisher's exact two-sided P=0.009); three of the cases with GPHN deletions in this study were diagnosed with ASD (PMID 23393157). Additional deletions in the GPHN gene have been identified in cases with ASD (PMIDs 23275889, 23632794, 24643514) and epilepsy (PMID 24561070); however, GPHN deletions display incomplete segregation with disease in some families, and their functional effect remains largely unclear.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Screening of 8775 cases with ASD, schizophrenia, or epilepsy and 27,019 controls for GPHN deletions determined that experimentally validated deletions in GPHN were significantly greater in cases than in controls (6/8,775 vs. 3/27,019; Fisher's exact two-sided P=0.009); three of the cases with GPHN deletions in this study were diagnosed with ASD (PMID 23393157). Additional deletions in the GPHN gene have been identified in cases with ASD (PMIDs 23275889, 23632794, 24643514) and epilepsy (PMID 24561070); however, GPHN deletions display incomplete segregation with disease in some families, and their functional effect remains largely unclear.

Reports Added
[New Scoring Scheme]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Screening of 8775 cases with ASD, schizophrenia, or epilepsy and 27,019 controls for GPHN deletions determined that experimentally validated deletions in GPHN were significantly greater in cases than in controls (6/8,775 vs. 3/27,019; Fisher's exact two-sided P=0.009); three of the cases with GPHN deletions in this study were diagnosed with ASD (PMID 23393157). Additional deletions in the GPHN gene have been identified in cases with ASD (PMIDs 23275889, 23632794, 24643514) and epilepsy (PMID 24561070); however, GPHN deletions display incomplete segregation with disease in some families, and their functional effect remains largely unclear.

Reports Added
[A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.2013] [Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.2014] [Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy.2015] [Forebrain-specific loss of synaptic GABAA receptors results in altered neuronal excitability and synaptic plasticity in mice.2016] [Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Screening of 8775 cases with ASD, schizophrenia, or epilepsy and 27,019 controls for GPHN deletions determined that experimentally validated deletions in GPHN were significantly greater in cases than in controls (6/8,775 vs. 3/27,019; Fisher's exact two-sided P=0.009); three of the cases with GPHN deletions in this study were diagnosed with ASD (PMID 23393157). Additional deletions in the GPHN gene have been identified in cases with ASD (PMIDs 23275889, 23632794, 24643514) and epilepsy (PMID 24561070); however, GPHN deletions display incomplete segregation with disease in some families, and their functional effect remains largely unclear.

Reports Added
[A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.2013] [Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.2014] [Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy.2015] [Forebrain-specific loss of synaptic GABAA receptors results in altered neuronal excitability and synaptic plasticity in mice.2016]
4/1/2015
icon
3

Increased from to 3

Description

Screening of 8775 cases with ASD, schizophrenia, or epilepsy and 27,019 controls for GPHN deletions determined that experimentally validated deletions in GPHN were significantly greater in cases than in controls (6/8,775 vs. 3/27,019; Fisher's exact two-sided P=0.009); three of the cases with GPHN deletions in this study were diagnosed with ASD (PMID 23393157). Additional deletions in the GPHN gene have been identified in cases with ASD (PMIDs 23275889, 23632794, 24643514) and epilepsy (PMID 24561070); however, GPHN deletions display incomplete segregation with disease in some families, and their functional effect remains largely unclear.

Krishnan Probability Score

Score 0.49147333169459

Ranking 5520/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99998147280508

Ranking 501/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94539321224278

Ranking 16452/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 8

Ranking 225/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.1076146721476

Ranking 5969/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ARHGEF9 Cdc42 guanine nucleotide exchange factor (GEF) 9 Human Protein Binding 23229 B1AMR3
GLRB glycine receptor, beta Human Protein Binding 2743 P48167
KLKB1 Plasma kallikrein Human Protein Binding 3818 P03952
KMO Kynurenine 3-monooxygenase Human Protein Binding 8564 O15229-2
ODF3L2 outer dense fiber of sperm tails 3-like 2 Human Protein Binding 284451 Q3SX64
PCK1 phosphoenolpyruvate carboxykinase 1 (soluble) Human Protein Binding 5105 P35558
SPATS1 spermatogenesis associated, serine-rich 1 Human Protein Binding 221409 Q496A3
STS steroid sulfatase (microsomal), isozyme S Human Protein Binding 412 P08842
TSSK1B Testis-specific serine/threonine-protein kinase 1 Human Protein Binding 83942 Q9BXA7
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