Human Gene Module / Chromosome 18 / CELF4

CELF4CUGBP, Elav-like family member 4

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 15
Rare Variants / Common Variants
15 / 0
EAGLE Score
8.5
Moderate Learn More
Aliases
CELF4, BRUNOL-4,  BRUNOL4
Associated Syndromes
-
Chromosome Band
18q12.2
Associated Disorders
DD/NDD, EP, EPS
Genetic Category
Rare Single Gene Mutation, Functional
Relevance to Autism

A complex de novo chromosomal rearrangement disrupting the CELF4 gene was identified in a male patient with borderline IQ, developmental and behavioral disorders (inlcuding autistic behavior), myopia, obesity, and febrile seizures in childhood (Halgren et al., 2012). Two de novo loss-of-function (LoF) variants in this gene have been identified in ASD probands (Krumm et al., 2015; Lim et al., 2017). A familial 18q12.2 deletion with a distal breakpoint within intron 2 of the CELF4 gene was identified in a 7-year-old female proband diagnosed with autism and syndromic intellectual disability and her mother, who presented with intellectual disability and autistic behavior (Barone et al., 2017).

Molecular Function

RNA-binding protein implicated in the regulation of pre-mRNA alternative splicing. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. When expressed ubiquitously, CELF4 is strongly expressed in the cerebellum, hippocampus, amygdala, temporal and frontal cortex and frontal lobes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CELF4 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Complex seizure disorder caused by Brunol4 deficiency in mice Yang Y , et al. (2007) No -
2 Support Etiology of a genetically complex seizure disorder in Celf4 mutant mice Wagnon JL , et al. (2011) No -
3 Primary Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity Halgren C , et al. (2012) No DD
4 Support Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice Sun W , et al. (2012) No -
5 Support CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function Wagnon JL , et al. (2012) No -
6 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
7 Support Familial 18q12.2 deletion supports the role of RNA-binding protein CELF4 in autism spectrum disorders Barone R , et al. (2017) Yes Epilepsy/seizures
8 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
9 Support Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes Halgren C , et al. (2018) No -
10 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
11 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
12 Support - Rodin RE et al. (2021) Yes -
13 Support - Mahjani B et al. (2021) Yes -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Iva Salamon et al. (2023) No -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - complex_structural_alteration De novo - - 29805044 Halgren C , et al. (2018)
c.173T>C p.Ile58Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.296T>G p.Phe99Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.629A>G p.Asn210Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.509G>T p.Arg170Leu missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1129C>T p.Gln377Ter stop_gained De novo - Simplex 28714951 Lim ET , et al. (2017)
c.493G>T p.Glu165Ter stop_gained De novo - Simplex 25961944 Krumm N , et al. (2015)
- - complex_structural_alteration De novo - Simplex 22617346 Halgren C , et al. (2012)
c.1246+39C>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1330+64G>A - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.610G>C p.Glu204Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multi-generational 28407444 Barone R , et al. (2017)
c.1120C>G p.Pro374Ala missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.744G>T p.Met248Ile missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
ENSG00000101489:ENST00000361795:exon1:c.A29G:p.N10S,ENSG00000101489:ENST00000601392:exon1:c.A29G:p.N - missense_variant De novo - - 33432195 Rodin RE et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

4/1/2022
2
icon
1

Decreased from 2 to 1

1/1/2021
2
icon
2

Decreased from 2 to 2

Description

A complex de novo chromosomal rearrangement disrupting the CELF4 gene was identified in a male patient with borderline IQ, developmental and behavioral disorders (inlcuding autistic behavior), myopia, obesity, and febrile seizures in childhood (Halgren et al., 2012). Two de novo loss-of-function (LoF) variants in this gene have been identified in ASD probands (Krumm et al., 2015; Lim et al., 2017). A familial 18q12.2 deletion with a distal breakpoint within intron 2 of the CELF4 gene was identified in a 7-year-old female proband diagnosed with autism and syndromic intellectual disability and her mother, who presented with intellectual disability and autistic behavior (Barone et al., 2017).

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
1/1/2020
2
icon
2

Decreased from 2 to 2

Description

A complex de novo chromosomal rearrangement disrupting the CELF4 gene was identified in a male patient with borderline IQ, developmental and behavioral disorders (inlcuding autistic behavior), myopia, obesity, and febrile seizures in childhood (Halgren et al., 2012). Two de novo loss-of-function (LoF) variants in this gene have been identified in ASD probands (Krumm et al., 2015; Lim et al., 2017). A familial 18q12.2 deletion with a distal breakpoint within intron 2 of the CELF4 gene was identified in a 7-year-old female proband diagnosed with autism and syndromic intellectual disability and her mother, who presented with intellectual disability and autistic behavior (Barone et al., 2017).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A complex de novo chromosomal rearrangement disrupting the CELF4 gene was identified in a male patient with borderline IQ, developmental and behavioral disorders (inlcuding autistic behavior), myopia, obesity, and febrile seizures in childhood (Halgren et al., 2012). Two de novo loss-of-function (LoF) variants in this gene have been identified in ASD probands (Krumm et al., 2015; Lim et al., 2017). A familial 18q12.2 deletion with a distal breakpoint within intron 2 of the CELF4 gene was identified in a 7-year-old female proband diagnosed with autism and syndromic intellectual disability and her mother, who presented with intellectual disability and autistic behavior (Barone et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A complex de novo chromosomal rearrangement disrupting the CELF4 gene was identified in a male patient with borderline IQ, developmental and behavioral disorders (inlcuding autistic behavior), myopia, obesity, and febrile seizures in childhood (Halgren et al., 2012). Two de novo loss-of-function (LoF) variants in this gene have been identified in ASD probands (Krumm et al., 2015; Lim et al., 2017). A familial 18q12.2 deletion with a distal breakpoint within intron 2 of the CELF4 gene was identified in a 7-year-old female proband diagnosed with autism and syndromic intellectual disability and her mother, who presented with intellectual disability and autistic behavior (Barone et al., 2017).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2017
icon
3

Increased from to 3

Description

A complex de novo chromosomal rearrangement disrupting the CELF4 gene was identified in a male patient with borderline IQ, developmental and behavioral disorders (inlcuding autistic behavior), myopia, obesity, and febrile seizures in childhood (Halgren et al., 2012). Two de novo loss-of-function (LoF) variants in this gene have been identified in ASD probands (Krumm et al., 2015; Lim et al., 2017). A familial 18q12.2 deletion with a distal breakpoint within intron 2 of the CELF4 gene was identified in a 7-year-old female proband diagnosed with autism and syndromic intellectual disability and her mother, who presented with intellectual disability and autistic behavior (Barone et al., 2017).

Krishnan Probability Score

Score 0.50216703755193

Ranking 1983/25841 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 0.97436473019522

Ranking 2268/18225 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 0.94083956323108

Ranking 14713/18665 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 0.25590093404863

Ranking 3390/20870 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
Submit New Gene

Report an Error