Human Gene Module / Chromosome 17 / RAI1

RAI1retinoic acid induced 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
9 / 24
Rare Variants / Common Variants
15 / 1
Aliases
RAI1, SMS,  SMCR,  KIAA1820,  MGC12824
Associated Syndromes
Smith-Magenis syndrome, Potocki-Lupski syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
17p11.2
Associated Disorders
EPS, ID
Relevance to Autism

Studies have found rare mutations in the RAI1 gene that are associated with autism. In addition, RAI1 variants have been associated with Potocki-Lupski and Smith-Magenis syndromes.

Molecular Function

Mutations in RAI1 cause Smith-Magenis Syndrome.

Reports related to RAI1 (24 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in RAI1 associated with Smith-Magenis syndrome. Slager RE , et al. (2003) No -
2 Primary Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay. Nakamine A , et al. (2007) Yes -
3 Highly Cited Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism... Potocki L , et al. (2007) No -
4 Recent Recommendation How much is too much? Phenotypic consequences of Rai1 overexpression in mice. Girirajan S , et al. (2008) No -
5 Recent Recommendation Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice. Girirajan S and Elsea SH (2009) No -
6 Support Gene-network analysis identifies susceptibility genes related to glycobiology in autism. van der Zwaag B , et al. (2009) Yes -
7 Recent Recommendation Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage sensitive loci also associated... Williams SR , et al. (2009) No -
8 Recent Recommendation Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in ... Zhang F , et al. (2010) No -
9 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut... Koshimizu E , et al. (2013) Yes ID, epilepsy
10 Highly Cited Interstitial deletion of (17)(p11.2p11.2) in nine patients. Smith AC , et al. (1986) No -
11 Support Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA recep... Adams DR , et al. (2014) No Hypoglycemia, lactic acidosis
12 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
13 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
14 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
15 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
16 Recent Recommendation Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. Haybaeck J , et al. (2015) No -
17 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
18 Recent Recommendation Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Huang WH , et al. (2016) No -
19 Recent Recommendation Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice. Rao NR , et al. (2017) No -
20 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No Behavioral disorder (including stereotypies)
21 Support A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome ... Abad C , et al. (2018) Yes -
22 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
23 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes -
24 Support RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling Garay PM et al. (2020) No -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain - - - 20188345 Zhang F , et al. (2010)
- - copy_number_loss Unknown - - 32477112 Lee J et al. (2020)
- - copy_number_loss - - - 19492091 van der Zwaag B , et al. (2009)
- - copy_number_gain De novo NA - 17334992 Nakamine A , et al. (2007)
c.2273G>A p.Trp758Ter stop_gained De novo NA - 24863970 Adams DR , et al. (2014)
c.1664C>T p.Thr555Ile missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.2347G>A p.Asp783Asn missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.3440G>A p.Arg1147Gln missense_variant De novo NA Simplex 29794985 Abad C , et al. (2018)
c.1148C>T p.Pro383Leu missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.4238T>C p.Met1413Thr missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.2966_2969del p.Lys989SerfsTer74 frameshift_variant De novo NA - 28708303 Chrot E , et al. (2017)
c.3575del p.Ser1192ThrfsTer8 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.2332_2336del p.Gly778GlnfsTer7 frameshift_variant De novo NA Simplex 25167861 Redin C , et al. (2014)
c.412del p.Val138TrpfsTer8 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1471G>A p.Glu491Lys missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
N/A N/A copy_number_gain - - - 20188345 Zhang F , et al. (2010)
SFARI Gene score
1

High Confidence

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018.

Score Delta: Score remained at 3S

1

High Confidence

See all Category 1 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.

7/1/2020
3S
icon
3S

Score remained at 3S

Description

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018.

4/1/2020
3S
icon
3S

Score remained at 3S

Description

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018.

1/1/2020
3S
icon
3S

Score remained at 3S

Description

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018.

10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018.

Reports Added
[New Scoring Scheme]
7/1/2018
3.3 + S
icon
3S

Decreased from 3.3 + S to 3S

Description

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018.

7/1/2017
S
icon
S

Increased from S to S

Description

RAI1 is included in a region that is duplicated in an individual with autism/MR, and shows altered gene expression (PMID: 17334992). It was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. There is no evidence implicating it in idiopathic autism.

4/1/2017
S
icon
S

Increased from S to S

Description

RAI1 is included in a region that is duplicated in an individual with autism/MR, and shows altered gene expression (PMID: 17334992). It was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. There is no evidence implicating it in idiopathic autism.

Reports Added
[Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay.2007] [Gene-network analysis identifies susceptibility genes related to glycobiology in autism.2009] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in ...2010] [Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage sensitive loci also associated...2009] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in RAI1 associated with Smith-Magenis syndrome.2003] [How much is too much? Phenotypic consequences of Rai1 overexpression in mice.2008] [Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice.2009] [Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome.2016] [Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice.2017]
10/1/2016
S
icon
S

Increased from S to S

Description

RAI1 is included in a region that is duplicated in an individual with autism/MR, and shows altered gene expression (PMID: 17334992). It was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. There is no evidence implicating it in idiopathic autism.

1/1/2016
S
icon
S

Increased from S to S

Description

RAI1 is included in a region that is duplicated in an individual with autism/MR, and shows altered gene expression (PMID: 17334992). It was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. There is no evidence implicating it in idiopathic autism.

Reports Added
[Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay.2007] [Gene-network analysis identifies susceptibility genes related to glycobiology in autism.2009] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in ...2010] [Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage sensitive loci also associated...2009] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in RAI1 associated with Smith-Magenis syndrome.2003] [How much is too much? Phenotypic consequences of Rai1 overexpression in mice.2008] [Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice.2009] [Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
1/1/2015
S
icon
S

Increased from S to S

Description

RAI1 is included in a region that is duplicated in an individual with autism/MR, and shows altered gene expression (PMID: 17334992). It was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. There is no evidence implicating it in idiopathic autism.

Krishnan Probability Score

Score 0.4818310536303

Ranking 7890/25841 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 0.99913611187699

Ranking 1035/18225 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
Iossifov Probability Score

Score 0.983

Ranking 41/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.32388577342716

Ranking 199/18665 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).
Zhang D Score

Score 0.40262137298965

Ranking 1432/20870 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.
CNVs associated with RAI1(1 CNVs)
17p11.2 49 Deletion-Duplication 68  /  317
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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