Human Gene Module / Chromosome X / IL1RAPL1

IL1RAPL1interleukin 1 receptor accessory protein-like 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 27
Rare Variants / Common Variants
28 / 0
Aliases
IL1RAPL1, IL1R8,  MRX21,  MRX34,  OPHN4,  IL1RAPL,  TIGIRR-2
Associated Syndromes
-
Chromosome Band
Xp21.3-p21.2
Associated Disorders
DD/NDD, ID, ASD, EPS
Relevance to Autism

Studies have found rare mutations in the IL1RAPL1 gene that are associated with autism (e.g. Bhat et al., 2008) as well as with developmental delay and intellectual disability (Mikhail et al., 2011).

Molecular Function

This protein may regulate calcium-dependent exocytosis.

SFARI Genomic Platforms
Reports related to IL1RAPL1 (27 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis Bahi N , et al. (2003) No -
2 Recent Recommendation IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation Gambino F , et al. (2007) No -
3 Primary Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism Bhat SS , et al. (2007) Yes -
4 Recent Recommendation A study on the correlation between IL1RAPL1 and human cognitive ability Gao X , et al. (2008) No -
5 Support Mutations in the calcium-related gene IL1RAPL1 are associated with autism Piton A , et al. (2008) Yes MR
6 Recent Recommendation A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation Pavlowsky A , et al. (2010) No -
7 Support Functional impact of global rare copy number variation in autism spectrum disorders Pinto D , et al. (2010) Yes -
8 Support Direct measure of the de novo mutation rate in autism and schizophrenia cohorts Awadalla P , et al. (2010) Yes -
9 Recent Recommendation Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders Mikhail FM , et al. (2011) No ID
10 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
11 Support Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems Barone C , et al. (2013) No ASD
12 Recent Recommendation IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway Hayashi T , et al. (2013) No -
13 Support Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases Pham J , et al. (2014) Yes -
14 Support Etiological yield of SNP microarrays in idiopathic intellectual disability Utine GE , et al. (2014) No ASD or autistic features, epilepsy
15 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
16 Recent Recommendation Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis Ramos-Brossier M , et al. (2014) No DD
17 Support Whole exome sequencing in females with autism implicates novel and candidate genes Butler MG , et al. (2015) Yes -
18 Support X-linked intellectual disability related genes disrupted by balanced X-autosome translocations Moyss-Oliveira M , et al. (2015) No -
19 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
20 Recent Recommendation The X-Linked Intellectual Disability Protein IL1RAPL1 Regulates Dendrite Complexity Montani C , et al. (2017) No -
21 Support Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder Du X , et al. (2018) Yes DD/ID, epilepsy/seizures
22 Support Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes Moyss-Oliveira M , et al. (2019) No -
23 Recent Recommendation Genome-wide detection of tandem DNA repeats that are expanded in autism Trost B et al. (2020) Yes -
24 Support - Rasheed M et al. (2021) No -
25 Support - N.Y.) (07/2) No -
26 Support - Miyake N et al. (2023) Yes -
27 Support - Spataro N et al. (2023) No Autistic features
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_gain De novo - - 24508361 Utine GE , et al. (2014)
- - inversion Familial Maternal - 18005360 Bhat SS , et al. (2007)
- - minisatellite Unknown - Unknown 32717741 Trost B et al. (2020)
- - copy_number_loss Unknown - Unknown 24398791 Pham J , et al. (2014)
- - translocation De novo - - 26290131 Moyss-Oliveira M , et al. (2015)
- - translocation De novo - - 30700833 Moyss-Oliveira M , et al. (2019)
c.263C>T p.Pro88Leu missense_variant De novo - - 35901164 N.Y.) (07/2)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Simplex 23613341 Barone C , et al. (2013)
- - copy_number_loss Familial Maternal - 22031302 Mikhail FM , et al. (2011)
- - copy_number_loss Familial Maternal Multiplex 18801879 Piton A , et al. (2008)
- - copy_number_gain Familial Maternal Multiplex 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20531469 Pinto D , et al. (2010)
c.1489C>T p.Arg497Ter stop_gained De novo - Simplex 30555518 Du X , et al. (2018)
- - copy_number_loss Familial Maternal Multiplex 34452636 Rasheed M et al. (2021)
c.779-65850del - frameshift_variant De novo - - 20797689 Awadalla P , et al. (2010)
c.1046T>C p.Leu349Pro missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.1136A>G p.Lys379Arg missense_variant Familial Maternal - 18801879 Piton A , et al. (2008)
c.1854A>T p.Gln618His missense_variant Familial Maternal - 18801879 Piton A , et al. (2008)
c.1433C>A p.Thr478Asn missense_variant Unknown - Multiplex 25574603 Butler MG , et al. (2015)
c.1918C>T p.Leu640Phe missense_variant Familial Maternal Simplex 36973392 Miyake N et al. (2023)
c.1730del p.Glu577GlyfsTer24 frameshift_variant De novo - Simplex 18801879 Piton A , et al. (2008)
c.91T>C p.Cys31Arg missense_variant Familial Maternal Multiplex 25305082 Ramos-Brossier M , et al. (2014)
c.894_903del p.Trp299ThrfsTer18 frameshift_variant Familial Maternal Multiplex 25167861 Redin C , et al. (2014)
c.703+99897_778+59920del p.Ala235_Leu259del copy_number_loss Familial Maternal Multiplex 25305082 Ramos-Brossier M , et al. (2014)
c.1213_1287del p.Tyr405_Phe429del copy_number_loss Familial Maternal and paternal Multi-generational 25305082 Ramos-Brossier M , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

7/1/2020
3
icon
3

Decreased from 3 to 3

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

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

Decreased from 4 to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

Reports Added
[Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism.2007] [Mutations in the calcium-related gene IL1RAPL1 are associated with autism.2008] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Whole exome sequencing in females with autism implicates novel and candidate genes.2015] [Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.2014] [IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exoc...2003] [IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+channel and neurite elongation.2007] [A study on the correlation between IL1RAPL1 and human cognitive ability.2008] [A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation.2010] [IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons thro...2013] [X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.2015] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [The X-linked intellectual disability protein IL1RAPL1 regulates dendrite complexity.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

Reports Added
[Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism.2007] [Mutations in the calcium-related gene IL1RAPL1 are associated with autism.2008] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Whole exome sequencing in females with autism implicates novel and candidate genes.2015] [Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.2014] [IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exoc...2003] [IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+channel and neurite elongation.2007] [A study on the correlation between IL1RAPL1 and human cognitive ability.2008] [A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation.2010] [IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons thro...2013] [X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.2015]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

10/1/2014
4
icon
4

Decreased from 4 to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

7/1/2014
No data
icon
4

Increased from No data to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Studies have identified rare sequence variants in the IL1RAPL1 gene with autism (e.g. Bhat et al., 2008).

Krishnan Probability Score

Score 0.58575496388076

Ranking 519/25841 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 0.99689367835644

Ranking 1375/18225 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 0.94975040127291

Ranking 18217/18665 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 20

Ranking 103/461 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 0.50848229013408

Ranking 459/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
NCS-1 neuronal calcium sensor 1 Human Protein Binding 23413 P62166
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