Human Gene Module / Chromosome 15 / LEO1

LEO1LEO1 homolog, Paf1/RNA polymerase II complex component

Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 3
Rare Variants / Common Variants
5 / 0
Associated Syndromes
Genetic Category
Rare Single Gene Mutation
Chromosome Band
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.

Reports related to LEO1 (3 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. Deciphering Developmental Disorders Study (2017) No -
3 Recent Recommendation Paternally inherited cis-regulatory structural variants are associated with autism. Brandler WM , et al. (2018) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1663C>T p.Arg555Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
delG - frameshift_variant De novo - - 28135719 Deciphering Developmental Disorders Study (2017)
C>A - missense_variant De novo - - 28135719 Deciphering Developmental Disorders Study (2017)
- - copy_number_loss Familial Paternal Simplex 29674594 Brandler WM , et al. (2018)
- - copy_number_loss Familial Paternal Multiplex 29674594 Brandler WM , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score

Strong Candidate



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.


Initial score established: 2.4



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: A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at
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 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: aned_exac_nonTCGA_z_pli_rec_null_data.txt
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
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.
CNVs associated with LEO1(1 CNVs)
15q21.2 9 Deletion-Duplication 16  /  25
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