Human Gene Module / Chromosome 17 / RAI1

RAI1retinoic acid induced 1

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
7 / 21
Rare Variants / Common Variants
13 / 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
ID, EPS
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 (21 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 -
Rare Variants   (13)
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 - - - 19492091 van der Zwaag B , et al. (2009)
- - copy_number_gain De novo - - 17334992 Nakamine A , et al. (2007)
c.2273G>A p.Trp758Ter stop_gained De novo - - 24863970 Adams DR , et al. (2014)
3574+G 1192-! frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1664C>T p.Thr555Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2347G>A p.Asp783Asn missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3440G>A p.Arg1147Gln missense_variant De novo - 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 - - 28708303 Chrot E , et al. (2017)
c.2332_2336del p.Gly778GlnfsTer7 frameshift_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.1471G>A p.Glu491Lys missense_variant De novo - 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
3S

Suggestive Evidence, Syndromic

3S

Score Delta: Increased from S to 3.3 + S

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

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 disorder.2014] [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 disorder.2014] [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 45 Deletion-Duplication 64  /  305
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