Human Gene Module / Chromosome 1 / RERE

REREArginine-glutamic acid dipeptide (RE) repeats

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
13 / 18
Rare Variants / Common Variants
36 / 1
EAGLE Score
6.5
Moderate Learn More
Aliases
RERE, RP11-141M15.2,  ARG,  ARP,  ATN1L,  DNB1
Associated Syndromes
-
Chromosome Band
1p36.23
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

Two novel overlapping CNVs involving the RERE gene were identified in unrelated ASD cases (Prasad et al., 2012).

Molecular Function

Plays a role as a transcriptional repressor during development and may play a role in the control of cell survival. Overexpression of RERE recruits BAX to the nucleus particularly to POD and triggers caspase-3 activation, leading to cell death

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RERE (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Recent Recommendation De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions Fregeau B , et al. (2016) No ASD
5 Support Genotype-phenotype correlations in individuals with pathogenic RERE variants Jordan VK , et al. (2018) No ASD
6 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
7 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Niehaus AD et al. (2022) Yes ADHD, ID
11 Support - George A et al. (2022) No -
12 Support - Hu C et al. (2023) Yes -
13 Support - Cirnigliaro M et al. (2023) Yes -
14 Support - Lowther C et al. (2023) Yes -
15 Support - Karthika Ajit Valaparambil et al. () Yes -
16 Support - Qian Li et al. (2024) No Autistic behavior
17 Support - Omri Bar et al. (2024) Yes ADHD, OCD
18 Support - Karen Lob et al. () Yes ADHD, DD
Rare Variants   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 29330883 Jordan VK , et al. (2018)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Simplex 37595579 Lowther C et al. (2023)
c.1448-4C>A - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.49C>T p.Arg17Ter stop_gained De novo - - 31452935 Feliciano P et al. (2019)
- - copy_number_gain Familial Paternal Simplex 23275889 Prasad A , et al. (2013)
c.3623C>T p.Ala1208Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Unknown Not maternal Simplex 23275889 Prasad A , et al. (2013)
c.2278C>T p.Gln760Ter stop_gained De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1411G>A p.Val471Ile missense_variant De novo - - 27087320 Fregeau B , et al. (2016)
c.3466G>A p.Gly1156Arg missense_variant De novo - - 27087320 Fregeau B , et al. (2016)
c.3785C>G p.Pro1262Arg missense_variant De novo - - 27087320 Fregeau B , et al. (2016)
c.4293C>G p.His1431Gln missense_variant De novo - - 27087320 Fregeau B , et al. (2016)
c.3146C>T p.Pro1049Leu missense_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.3292C>G p.Leu1098Val missense_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.4303C>T p.His1435Tyr missense_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.4304A>G p.His1435Arg missense_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.4304A>T p.His1435Leu missense_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.4391A>G p.His1464Arg missense_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.3772G>A p.Glu1258Lys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3946G>A p.Glu1316Lys missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.248dup p.Ser84ValfsTer4 frameshift_variant De novo - - 29330883 Jordan VK , et al. (2018)
c.3249del p.Ser1084ArgfsTer173 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2728C>T p.Gln910Ter stop_gained De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3329C>A p.Pro1110Gln missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4300T>C p.Ser1434Pro missense_variant De novo - Simplex 36053530 Niehaus AD et al. (2022)
c.2270_2271dup p.Thr758GlyfsTer73 frameshift_variant De novo - - 39136901 Karen Lob et al. ()
c.3265C>A p.Pro1089Thr missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.3732del p.Tyr1245ThrfsTer12 frameshift_variant De novo - Simplex 38018232 Qian Li et al. (2024)
c.1978G>A p.Glu660Lys missense_variant Familial Maternal Multiplex 38256266 Omri Bar et al. (2024)
c.1104del p.Leu369CysfsTer16 frameshift_variant Unknown Not maternal - 27087320 Fregeau B , et al. (2016)
c.1512dup p.Tyr505ValfsTer37 frameshift_variant Familial Maternal Simplex 36053530 Niehaus AD et al. (2022)
c.4313_4314insTCCACC p.Leu1438_His1439insProPro inframe_insertion De novo - - 27087320 Fregeau B , et al. (2016)
c.4313_4314insTCCACC p.Leu1438_His1439insProPro inframe_insertion De novo - - 29330883 Jordan VK , et al. (2018)
c.3122del p.Pro1041LeufsTer40 frameshift_variant Unknown - Multi-generational 27087320 Fregeau B , et al. (2016)
c.2249_2250insCTCCCTCCTCAGCTCCTCCAGG p.Pro751SerfsTer43 frameshift_variant De novo - Multiplex 27087320 Fregeau B , et al. (2016)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1448-87delT;c.-215-87delT;c.1322-87delT;c.644-87delT - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

S

Syndromic

See all Category S Genes

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."

10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Novel recurrent/overlapping RERE CNVs (a paternally-inherited duplication and a deletion of unknown origin, both within an intronic region of the RERE gene) were identified in ASD probands in Prasad et al., 2012. A de novo likely gene-disruptive variant and a de novo predicted damaging missense variant were identified in RERE in ASD probands from the Simons Simplex Collection and Autism Sequencing Consortium, respectively (Krumm et al., 2015; De Rubeis et al., 2014). Phenotypic characterization of 10 individuals with putatively damaging RERE variants (one of whom was the SSC proband from Krumm et al.) identified a genetic syndrome characterized by neurodevelopmental disorders (developmental delay, intellectual disability and/or autism), hypotonia, seizures, behavioral problems, structural brain abnormalities, opthalmologic anomalies, congenital heart defects, and genitourinary abnormalities) (Fregeau et al., 2016). The phenotypic features of individuals with RERE variants overlap with those exhibited by individuals with proximal 1p36 deletions, suggesting that RERE haploinsufficiency is responsible for many of the phenotypes associated with 1p36 deletion syndrome. Jordan et al., 2018 described genotype-phenotype correlations in nine novel individuals with RERE variants; two of the nine individuals in this study were reported to have been diagnosed with autism spectrum disorder. An additional de novo likely gene-disruptive variant in the RERE gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
4/1/2016
icon
4S

Increased from to 4S

Description

Novel recurrent/overlapping RERE CNVs (a paternally-inherited duplication and a deletion of unknown origin, both within an intronic region of the RERE gene) were identified in ASD probands in Prasad et al., 2012. A de novo LoF variant and a de novo predicted damaging missense variant were identified in RERE in ASD probands from the Simons Simplex Collection and Autism Sequencing Consortium, respectively (Krumm et al., 2015; De Rubeis et al., 2014). Phenotypic characterization of 10 individuals with putatively damaging RERE variants (one of whom was the SSC proband from Krumm et al.) identified a genetic syndrome characterized by neurodevelopmental disorders (developmental delay, intellectual disability and/or autism), hypotonia, seizures, behavioral problems, structural brain abnormalities, opthalmologic anomalies, congenital heart defects, and genitourinary abnormalities) (Fregeau et al., 2016). The phenotypic features of individuals with RERE variants overlap with those exhibited by individuals with proximal 1p36 deletions, suggesting that RERE haploinsufficiency is responsible for many of the phenotypes associated with 1p36 deletion syndrome.

Reports Added
[A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Excess of rare, inherited truncating mutations in autism.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions.2016]
Krishnan Probability Score

Score 0.59185468670154

Ranking 473/25841 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.
Original Source
ExAC Score

Score 0.99999565525825

Ranking 392/18225 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
Original Source
Sanders TADA Score

Score 0.95084905627603

Ranking 18652/18665 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).
Original Source
Zhang D Score

Score 0.00210159374608

Ranking 8629/20870 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.
Original Source
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