Human Gene Module / Chromosome 15 / ZWILCH

ZWILCHzwilchkinetochore protein

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
6 / 0
Aliases
ZWILCH, KNTC1AP,  hZwilch
Associated Syndromes
-
Chromosome Band
15q22.31
Associated Disorders
-
Relevance to Autism

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (a de novo frameshift variant in an SSC proband in Iossifov et al., 2014, and a de novo frameshift variant in an ASD proband from a multiplex family in Yuen et al., 2015).

Molecular Function

Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to ZWILCH (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
3 Recent Recommendation A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders Gonzalez-Mantilla AJ , et al. (2016) No -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1612G>A p.Gly538Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.592-5_592-4del - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.572-2A>G - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1345+2T>C - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.344_345insC p.Ser116PhefsTer7 frameshift_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.1364_1365insG p.Asn456LysfsTer3 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (a de novo frameshift variant in an SSC proband in Iossifov et al., 2014, and a de novo frameshift variant in an ASD proband from a multiplex family in Yuen et al., 2015).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (a de novo frameshift variant in an SSC proband in Iossifov et al., 2014, and a de novo frameshift variant in an ASD proband from a multiplex family in Yuen et al., 2015).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (a de novo frameshift variant in an SSC proband in Iossifov et al., 2014, and a de novo frameshift variant in an ASD proband from a multiplex family in Yuen et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (a de novo frameshift variant in an SSC proband in Iossifov et al., 2014, and a de novo frameshift variant in an ASD proband from a multiplex family in Yuen et al., 2015).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2016
icon
4

Increased from to 4

Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (a de novo frameshift variant in an SSC proband in Iossifov et al., 2014, and a de novo frameshift variant in an ASD proband from a multiplex family in Yuen et al., 2015).

Krishnan Probability Score

Score 0.26033472009754

Ranking 25571/25841 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 8.3116392180479E-6

Ranking 14302/18225 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 0.42437988887418

Ranking 312/18665 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 0.044782940710691

Ranking 7376/20870 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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