Human Gene Module / Chromosome 15 / OTUD7A

OTUD7AOTU deubiquitinase 7A

Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
2 / 0
OTUD7A, C15orf16,  C16ORF15,  CEZANNE2,  OTUD7
Associated Syndromes
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
Associated Disorders
Relevance to Autism

OTUD7A resides within the locus for 15q13.3 microdeletion syndrome (OMIM 612001). A recurrent 680 kb deletion affecting OTUD7A and CHRNA7 was identified in ten individuals from four unrelated families presenting with neurodevelopmental phenotypes including developmental delay, intellectual disability, and seizures (Shinawi et al., 2009). Two reports published in 2018 further implicated OTUD7A as a major contributor to the phenotypes observed in individuals with 15q13.3 microdeletion syndrome. Uddin et al., 2018 demonstrated that expression of wild-type OTUD7A in cortical neurons from a mouse model of 15q13.3 microdeletion syndrome [Df(h15q13)/+] rescued dendritic spine defects, whereas OTUD7A containing a de novo in-frame deletion variant that was identified in an ASD proband failed to do so. Yin et al., 2018 reported that OTUD7A knockout mice recapitulated many of the the phenotypes observed in Df(h15q13)-/- mice, including developmental delay, abnormal electroencephalography patterns and seizures, rediced ultrasonic vocalizations, impaired motor learning and motor coordination, and reduced acoustic startle.

Molecular Function

The protein encoded by this gene is a deubiquitinizing enzyme with deubiquitinating activity towards 'Lys-11'-linked polyubiquitin chains, as well as a possible tumor suppressor. The encoded protein acts on TNF receptor associated factor 6 (TRAF6) to control nuclear factor kappa B expression.

Reports related to OTUD7A (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Shinawi M , et al. (2009) No -
2 Primary OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome. Uddin M , et al. (2018) Yes -
3 Recent Recommendation Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3 Microdeletion Syndrome. Yin J , et al. (2018) No -
4 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Guo H , et al. (2018) Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2214_2223del p.Ala738fs frameshift_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.1474_1482del p.Asn492_Lys494del inframe_deletion De novo - Multiplex 29395074 Uddin M , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score

Suggestive Evidence



Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4.5 + acc

Initial score established: 4.5 + acc



Krishnan Probability Score

Score 0.46138310282127

Ranking 9383/25841 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 0.97459544138619

Ranking 2261/18225 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 0.94284890471288

Ranking 15462/18665 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 0.53701356720806

Ranking 299/20870 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 OTUD7A(1 CNVs)
15q13.3 66 Deletion-Duplication 102  /  417
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