Human Gene Module / Chromosome 15 / LEO1

LEO1LEO1 homolog, Paf1/RNA polymerase II complex component

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
26 / 0
Aliases
LEO1, RDL
Associated Syndromes
-
Chromosome Band
15q21.2
Associated Disorders
-
Relevance to Autism

A de novo nonsense variant in the LEO1 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; additional de novo variants in this gene were observed in individuals from the Deciphering Developmental Disorders study in 2017. Paternally-inherited deletions of the LEO1 promoter were detected in three affected individuals (one trio and one concordant sib pair) in Brandler et al., 2018; fibroblast cell lines derived from the concordant sib pair displayed increased LEO1 expression compared to control lines (p = 0.018).

Molecular Function

Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LEO1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
3 Recent Recommendation Paternally inherited cis-regulatory structural variants are associated with autism Brandler WM , et al. (2018) Yes -
4 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
5 Support - Noor Smal et al. () Yes ADHD, DD, ID
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1148G>T p.Ser383Ile missense_variant De novo - - 28135719 et al. (2017)
c.1276C>T p.Arg426Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.24C>G p.Phe8Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.30C>A p.Ser10Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.190G>T p.Asp64Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.959A>G p.Asp320Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.992C>T p.Pro331Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1233G>C p.Arg411Ser missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1444C>G p.Arg482Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1460C>T p.Thr487Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1624C>G p.Arg542Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1642C>T p.Arg548Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1660C>T p.Arg554Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1687C>T p.Arg563Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1663C>T p.Arg555Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss Familial Paternal Simplex 29674594 Brandler WM , et al. (2018)
c.1143del p.Leu382SerfsTer3 frameshift_variant De novo - - 28135719 et al. (2017)
- - copy_number_loss Familial Paternal Multiplex 29674594 Brandler WM , et al. (2018)
c.187G>T p.Gly63Ter stop_gained Unknown Not maternal - 33004838 Wang T et al. (2020)
c.1109G>A p.Gly370Glu missense_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.1411C>A p.Leu471Ile missense_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.1478C>G p.Pro493Arg missense_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.1519T>C p.Ser507Pro missense_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.122C>T p.Ser41Phe missense_variant De novo - Multiplex 38965372 Noor Smal et al. ()
c.814+1G>A - splice_site_variant Familial Paternal Simplex 38965372 Noor Smal et al. ()
c.1624C>T p.Arg542Cys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo nonsense variant in the LEO1 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; additional de novo variants in this gene were observed in individuals from the Deciphering Developmental Disorders study in 2017. Paternally-inherited deletions of the LEO1 promoter were detected in three affected individuals (one trio and one concordant sib pair) in Brandler et al., 2018; fibroblast cell lines derived from the concordant sib pair displayed increased LEO1 expression compared to control lines (p = 0.018).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

10/1/2020
2
icon
2

Score remained at 2

Description

A de novo nonsense variant in the LEO1 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; additional de novo variants in this gene were observed in individuals from the Deciphering Developmental Disorders study in 2017. Paternally-inherited deletions of the LEO1 promoter were detected in three affected individuals (one trio and one concordant sib pair) in Brandler et al., 2018; fibroblast cell lines derived from the concordant sib pair displayed increased LEO1 expression compared to control lines (p = 0.018).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

A de novo nonsense variant in the LEO1 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; additional de novo variants in this gene were observed in individuals from the Deciphering Developmental Disorders study in 2017. Paternally-inherited deletions of the LEO1 promoter were detected in three affected individuals (one trio and one concordant sib pair) in Brandler et al., 2018; fibroblast cell lines derived from the concordant sib pair displayed increased LEO1 expression compared to control lines (p = 0.018).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
2

Increased from to 2

Description

A de novo nonsense variant in the LEO1 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; additional de novo variants in this gene were observed in individuals from the Deciphering Developmental Disorders study in 2017. Paternally-inherited deletions of the LEO1 promoter were detected in three affected individuals (one trio and one concordant sib pair) in Brandler et al., 2018; fibroblast cell lines derived from the concordant sib pair displayed increased LEO1 expression compared to control lines (p = 0.018).

Krishnan Probability Score

Score 0.43881597397587

Ranking 19960/25841 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 0.99960596971384

Ranking 890/18225 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 0.26324232008477

Ranking 152/18665 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 0.41920663373532

Ranking 1246/20870 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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