Human Gene Module / Chromosome 18 / KATNAL2

KATNAL2Katanin p60 subunit A-like 2

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
16 / 0
Aliases
KATNAL2, DKFZp667C165,  MGC33211
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
18q21.1
Associated Disorders
-
Relevance to Autism

De novo loss-of-function (LoF) variants in the KATNAL2 gene were identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified KATNAL2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo loss-of-function variant and a likely damaging de novo missense variant in KATNAL2 were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889).

Molecular Function

Severs microtubules in vitro in an ATP-dependent manner. This activity may promote rapid reorganization of cellular microtubule arrays

Reports related to KATNAL2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
3 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
5 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
6 Recent recommendation A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons. Williams MR , et al. (2016) No -
7 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.510+1G>A p.? splice_site_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
- p.? splice_site_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
del(G) - frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.310C>T p.Arg104Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
AC/A - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.673+1G>A - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.436C>T p.Arg146Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.730T>C p.Phe244Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.428G>A p.Arg143Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.740C>T p.Ala248Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1022G>A p.Arg341His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1045G>A p.Asp349Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.907C>T p.Arg303Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.157C>T p.Gln53Ter stop_gained Familial Maternal Multiplex 25621899 Yuen RK , et al. (2015)
c.429del p.Ser144GlnfsTer5 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.727T>C p.Phe243Leu missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

1

Score Delta: Score remained at 1.1

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.

1/1/2017
2
icon
1

Decreased from 2 to 1

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Two of these variants are stop-gains and many are missense variants in EVS. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KATNAL2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). A third de novo loss-of-function variant and a likely damaging de novo missense variant in KATNAL2 were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

4/1/2016
2
icon
2

Decreased from 2 to 2

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Two of these variants are stop-gains and many are missense variants in EVS. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KATNAL2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

1/1/2016
2
icon
2

Decreased from 2 to 2

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Two of these variants are stop-gains and many are missense variants in EVS. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KATNAL2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

1/1/2015
2
icon
2

Decreased from 2 to 2

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Two of these variants are stop-gains and many are missense variants in EVS. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KATNAL2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2014
3
icon
2

Decreased from 3 to 2

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Two of these variants are stop-gains and many are missense variants in EVS. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KATNAL2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
No data
icon
3

Increased from No data to 3

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Three of these variants are stop-gains and many are missense variants in EVS.

4/1/2014
No data
icon
3

Increased from No data to 3

Description

De novo variants in the KATNAL2 gene have been identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Three of these variants are stop-gains and many are missense variants in EVS.

Krishnan Probability Score

Score 0.49151855455652

Ranking 5473/25841 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.
ExAC Score

Score 0.00012586196908537

Ranking 12966/18225 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
Iossifov Probability Score

Score 0.85

Ranking 191/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.0063798003959267

Ranking 26/18665 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).
Larsen Cumulative Evidence Score

Score 39

Ranking 51/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.11731039432089

Ranking 5776/20870 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 KATNAL2(1 CNVs)
18q21.1 12 Deletion-Duplication 25  /  49
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
STRIP1 striatin interacting protein 1 Human Protein Binding 85369 Q5VSL9
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