OPHN1oligophrenin 1
Autism Reports / Total Reports
5 / 21Rare Variants / Common Variants
25 / 0Aliases
OPHN1, OPN1, MRX60, ARHGAP41Associated Syndromes
-Chromosome Band
Xq12Associated Disorders
SCZ, DD/NDD, EP, EPSRelevance to Autism
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
Molecular Function
A Rho-GTPase-activating protein involved in cell migration and outgrowth of axons and dendrites.
External Links
SFARI Genomic Platforms
Reports related to OPHN1 (21 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia | Philip N , et al. (2003) | No | - |
| 2 | Recent Recommendation | Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity | Khelfaoui M , et al. (2007) | No | - |
| 3 | Recent Recommendation | Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation | Khelfaoui M , et al. (2009) | No | - |
| 4 | Recent Recommendation | The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1 | Nakano-Kobayashi A , et al. (2009) | No | - |
| 5 | Recent Recommendation | The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors | Nadif Kasri N , et al. (2009) | No | - |
| 6 | Primary | Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia | Piton A , et al. (2010) | Yes | SCZ |
| 7 | Recent Recommendation | Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance | Al-Owain M , et al. (2010) | No | - |
| 8 | Support | Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE | Celestino-Soper PB , et al. (2011) | Yes | - |
| 9 | Support | A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations | Santos-Rebouas CB , et al. (2013) | No | - |
| 10 | Support | Genomic diagnosis for children with intellectual disability and/or developmental delay | Bowling KM , et al. (2017) | No | - |
| 11 | Support | Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice | Tumien B , et al. (2017) | No | - |
| 12 | Support | Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia | Moortgat S , et al. (2018) | No | Epilepsy/seizures, behavioral abnormalities |
| 13 | Support | Expanding the phenotypic spectrum associated with OPHN1 variants | Schwartz TS , et al. (2018) | No | DD, epilepsy/seizures |
| 14 | Support | Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes | Guo H , et al. (2018) | Yes | - |
| 15 | Support | Characterization of intellectual disability and autism comorbidity through gene panel sequencing | Aspromonte MC , et al. (2019) | Yes | - |
| 16 | Support | - | Pode-Shakked B et al. (2021) | No | Epilepsy/seizures |
| 17 | Support | - | Wang J et al. (2023) | Yes | - |
| 18 | Support | - | Sanchis-Juan A et al. (2023) | No | - |
| 19 | Support | - | Marketa Wayhelova et al. (2024) | No | - |
| 20 | Support | - | Isabelle Schrauwen et al. (2024) | No | - |
| 21 | Support | - | Axel Schmidt et al. (2024) | No | - |
Rare Variants (25)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | insertion | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
| c.184C>T | p.Gln62Ter | stop_gained | De novo | - | - | 12807966 | Philip N , et al. (2003) | |
| c.746T>C | p.Leu249Pro | missense_variant | De novo | - | - | 29286531 | Tumien B , et al. (2017) | |
| - | - | copy_number_loss | Familial | Maternal | Multiplex | 20528889 | Al-Owain M , et al. (2010) | |
| c.590T>A | p.Val197Glu | missense_variant | De novo | - | - | 29960046 | Schwartz TS , et al. (2018) | |
| c.542A>G | p.Tyr181Cys | missense_variant | Unknown | - | - | 39039281 | Axel Schmidt et al. (2024) | |
| c.1906C>G | p.Pro636Ala | missense_variant | De novo | - | Simplex | 37393044 | Wang J et al. (2023) | |
| c.2323G>A | p.Val775Met | missense_variant | De novo | - | - | 31209962 | Aspromonte MC , et al. (2019) | |
| c.2159-1G>C | - | splice_site_variant | De novo | - | Simplex | 34580403 | Pode-Shakked B et al. (2021) | |
| - | - | copy_number_loss | Familial | Maternal | Simplex | 21865298 | Celestino-Soper PB , et al. (2011) | |
| c.2114A>G | p.His705Arg | missense_variant | Familial | Maternal | - | 20479760 | Piton A , et al. (2010) | |
| c.1235G>A | p.Gly412Asp | missense_variant | Unknown | - | Simplex | 29510240 | Moortgat S , et al. (2018) | |
| c.170T>A | p.Val57Asp | missense_variant | De novo | - | Simplex | 34580403 | Pode-Shakked B et al. (2021) | |
| c.2035G>A | p.Asp679Asn | missense_variant | Familial | Maternal | - | 28554332 | Bowling KM , et al. (2017) | |
| c.549dup | p.Gln184SerfsTer23 | frameshift_variant | De novo | - | - | 29960046 | Schwartz TS , et al. (2018) | |
| c.374G>C | p.Gly125Ala | missense_variant | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
| c.2035G>A | p.Asp679Asn | missense_variant | Familial | Maternal | - | 29960046 | Schwartz TS , et al. (2018) | |
| c.697C>T | p.Gln233Ter | stop_gained | Familial | Maternal | Multiplex | 29510240 | Moortgat S , et al. (2018) | |
| c.931_932dup | p.Gln311HisfsTer7 | frameshift_variant | De novo | - | Simplex | 30504930 | Guo H , et al. (2018) | |
| - | - | copy_number_gain | Familial | Maternal | Multi-generational | 38755281 | Isabelle Schrauwen et al. (2024) | |
| dupAAGAATTC | - | frameshift_variant | Familial | Maternal | Multi-generational | 12807966 | Philip N , et al. (2003) | |
| c.384+3A>C | - | splice_site_variant | Familial | Maternal | Multi-generational | 29510240 | Moortgat S , et al. (2018) | |
| c.835del | p.Ala279LeufsTer2 | frameshift_variant | Familial | Maternal | - | 38321498 | Marketa Wayhelova et al. (2024) | |
| c.727C>T | p.Arg243Trp | missense_variant | Familial | Maternal | Multi-generational | 29510240 | Moortgat S , et al. (2018) | |
| c.781_891del | del37 | inframe_deletion | Familial | Maternal | Multi-generational | 24105372 | Santos-Rebouas CB , et al. (2013) |
Common Variants
No common variants reported.
SFARI Gene score
2
Strong Candidate
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe 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
2
Decreased from 3 to 2
New Scoring Scheme
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
Reports Added
[New Scoring Scheme]7/1/2019
3
3
Decreased from 3 to 3
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
10/1/2018
3
3
Decreased from 3 to 3
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
7/1/2018
3
3
Decreased from 3 to 3
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
4/1/2017
3
3
Decreased from 3 to 3
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
Reports Added
[Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.2010] [Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.2011] [Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia.2003] [A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations.2013] [Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance.2010] [Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine imma...2007] [Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation.2009] [The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1.2009] [The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors.2009] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]7/1/2014
No data
3
Increased from No data to 3
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
4/1/2014
No data
3
Increased from No data to 3
Description
Rare mutations in the OPHN1 gene have been identified with autism and schizophrenia (Piton et al., 2011; Celestino-Soper et al., 2011) as well as with congenital cerebellar hypoplasia (CCH) and mental retardation.
Krishnan Probability Score
Score 0.44382893012369
Ranking 16404/25841 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.
ExAC Score
Score 0.99944841455057
Ranking 950/18225 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
Sanders TADA Score
Score 0.94237907838945
Ranking 15284/18665 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).
Larsen Cumulative Evidence Score
Score 0
Ranking 452/461 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.
Zhang D Score
Score 0.49513244769824
Ranking 558/20870 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.