Human Gene Module / Chromosome X / OPHN1

OPHN1oligophrenin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 18
Rare Variants / Common Variants
22 / 0
Aliases
OPHN1, OPN1,  MRX60,  ARHGAP41
Associated Syndromes
-
Chromosome Band
Xq12
Associated Disorders
SCZ, DD/NDD, EP, EPS
Relevance 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.

SFARI Genomic Platforms
Reports related to OPHN1 (18 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 -
Rare Variants   (22)
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.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)
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.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

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

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
icon
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
icon
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
icon
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.

7/1/2014
No data
icon
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
icon
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.
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