Human Gene Module / Chromosome X / RLIM

RLIMRing finger protein, LIM domain interacting

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 6
Rare Variants / Common Variants
14 / 0
Aliases
RLIM, NY-REN-43,  RNF12
Associated Syndromes
-
Chromosome Band
Xq13.2
Associated Disorders
ASD
Relevance to Autism

A rare missense variant in the RLIM gene (c.1067A>G; p.Tyr356Cys) segregated with disease in a three-generation Norwegian family with a novel X-linked intellectual disability syndrome characterized by autism, subtle facial dysmorphism, and severe feeding problems (Tonne et al., 2015).

Molecular Function

The protein encoded by this gene is a E3 ubiquitin protein ligase that targets LIM domain binding 1 (LDB1/CLIM) for proteasome-dependent degradation1. This protein and LDB1 are co-repressors of LHX1/LIM-1, a homeodomain transcription factor. By targeting ZFP42 for degradation, RLIM acts as an activator of random inactivation of X chromosome in the embryo.

External Links
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Human
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Zebrafish
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SFARI Genomic Platforms
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Reports related to RLIM (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes Hu H et al. (2016) No -
2 Primary Syndromic X-linked intellectual disability segregating with a missense variant in RLIM Tnne E , et al. (2015) Yes -
3 Recent Recommendation Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder Frints SGM , et al. (2018) No -
4 Recent Recommendation RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation Bustos F , et al. (2018) No -
5 Recent Recommendation RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features Palmer EE et al. (2020) No ASD/autistic features
6 Support - Spataro N et al. (2023) No -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Maternal Simplex 33159883 Palmer EE et al. (2020)
- - copy_number_gain Familial Maternal Multiplex 33159883 Palmer EE et al. (2020)
- - copy_number_gain Familial Maternal Extended multiplex 33159883 Palmer EE et al. (2020)
- - copy_number_gain Familial Maternal Multi-generational 33159883 Palmer EE et al. (2020)
c.366G>C p.Trp122Cys missense_variant Familial Maternal - 36980980 Spataro N et al. (2023)
c.230C>T p.Pro77Leu missense_variant Familial Maternal Simplex 29728705 Frints SGM , et al. (2018)
c.1093C>T p.Arg365Cys missense_variant Familial Maternal Multiplex 29728705 Frints SGM , et al. (2018)
c.1159C>T p.Arg387Cys missense_variant Familial Maternal Multi-generational 25644381 Hu H et al. (2016)
c.1760C>G p.Pro587Arg missense_variant Familial Maternal Multi-generational 25644381 Hu H et al. (2016)
c.1795C>T p.Arg599Cys missense_variant Familial Maternal Multi-generational 25644381 Hu H et al. (2016)
c.1067A>G p.Tyr356Cys missense_variant Familial Maternal Multi-generational 25735484 Tnne E , et al. (2015)
c.1831C>T p.Arg611Cys missense_variant Familial Maternal Extended multiplex 29728705 Frints SGM , et al. (2018)
c.1729T>C p.Tyr577His missense_variant Familial Maternal Multi-generational 29728705 Frints SGM , et al. (2018)
c.1792G>A p.Asp598Asn missense_variant Familial Maternal Multi-generational 29728705 Frints SGM , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A rare missense variant in the RLIM gene (c.1067A>G; p.Tyr356Cys) segregated with disease in a three-generation Norwegian family with a novel X-linked intellectual disability syndrome characterized by autism, subtle facial dysmorphism, and severe feeding problems (Tonne et al., 2015). Missense variants in the RLIM gene that segregated with X-linked intellectual disability were also reported in three multi-generational pedigrees in Hu et al., 2016. Genetic and clinical findings of nine unrelated families with RLIM missense variants (the four previously identified families in Tonne et al., 2015 and Hu et al., 2016, and five previously unreported families) were reported in Frints et al., 2018; in addition to intellectual disability, a total of 40 affected males in these families frequently presented with variable behavioral anomalies (including autistic features or ASD, which was observed in 15/17 informative males) with or without congenital malformations. Functional characterization of ID-associated RLIM variants in Frints et al., 2018 and Bustos et al., 2018 demonstrated impairments in ligase activity and loss-of-function effects in rlim mutant zebrafish and mouse embryonic stem cells (mESCs).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2020
S
icon
S

Score remained at S

Description

A rare missense variant in the RLIM gene (c.1067A>G; p.Tyr356Cys) segregated with disease in a three-generation Norwegian family with a novel X-linked intellectual disability syndrome characterized by autism, subtle facial dysmorphism, and severe feeding problems (Tonne et al., 2015). Missense variants in the RLIM gene that segregated with X-linked intellectual disability were also reported in three multi-generational pedigrees in Hu et al., 2016. Genetic and clinical findings of nine unrelated families with RLIM missense variants (the four previously identified families in Tonne et al., 2015 and Hu et al., 2016, and five previously unreported families) were reported in Frints et al., 2018; in addition to intellectual disability, a total of 40 affected males in these families frequently presented with variable behavioral anomalies (including autistic features or ASD, which was observed in 15/17 informative males) with or without congenital malformations. Functional characterization of ID-associated RLIM variants in Frints et al., 2018 and Bustos et al., 2018 demonstrated impairments in ligase activity and loss-of-function effects in rlim mutant zebrafish and mouse embryonic stem cells (mESCs).

Reports Added
[RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A rare missense variant in the RLIM gene (c.1067A>G; p.Tyr356Cys) segregated with disease in a three-generation Norwegian family with a novel X-linked intellectual disability syndrome characterized by autism, subtle facial dysmorphism, and severe feeding problems (Tonne et al., 2015). Missense variants in the RLIM gene that segregated with X-linked intellectual disability were also reported in three multi-generational pedigrees in Hu et al., 2016. Genetic and clinical findings of nine unrelated families with RLIM missense variants (the four previously identified families in Tonne et al., 2015 and Hu et al., 2016, and five previously unreported families) were reported in Frints et al., 2018; in addition to intellectual disability, a total of 40 affected males in these families frequently presented with variable behavioral anomalies (including autistic features or ASD, which was observed in 15/17 informative males) with or without congenital malformations. Functional characterization of ID-associated RLIM variants in Frints et al., 2018 and Bustos et al., 2018 demonstrated impairments in ligase activity and loss-of-function effects in rlim mutant zebrafish and mouse embryonic stem cells (mESCs).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.44708790563266

Ranking 14091/25841 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 0.99177291457597

Ranking 1725/18225 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 0.93204285142401

Ranking 11868/18665 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 0.47595418634323

Ranking 695/20870 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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