Human Gene Module / Chromosome 1 / KIF14

KIF14kinesin family member 14

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
3 / 0
Aliases
KIF14, MCPH20,  MKS12
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
1q32.1
Associated Disorders
ASD
Relevance to Autism

A de novo missense variant in the KIF14 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KIF14 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 3 CNVs from SCZ cases (5 total) vs. 0 CNVs in controls (Odds ratio 6.55, P = 1.0E-05)].

Molecular Function

This gene encodes a member of the kinesin-3 superfamily of microtubule motor proteins. These proteins are involved in numerous processes including vesicle transport, chromosome segregation, mitotic spindle formation, and cytokinesis. Biallelic mutations in this gene are responsible for an autosomal recessive form of microcephaly (autosomal recessive primary microcephaly-20 or MCPH20; OMIM 617914); autistic features were reported in both affected siblings from one of four families with this disorder in Makrythanasis et al., 2018.

Reports related to KIF14 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
2 Primary Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
3 Support Biallelic variants in KIF14 cause intellectual disability with microcephaly. Makrythanasis P , et al. (2018) No Autistic features
4 Recent Recommendation Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Kushima I , et al. (2018) Yes -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 30208311 Kushima I , et al. (2018)
c.1367C>T p.Thr456Met missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.711G>A p.Thr237%3D synonymous_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant in the KIF14 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KIF14 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 3 CNVs from SCZ cases (5 total) vs. 0 CNVs in controls (Odds ratio 6.55, P = 1.0E-05)]. Biallelic mutations in this gene are responsible for an autosomal recessive form of microcephaly (autosomal recessive primary microcephaly-20 or MCPH20; OMIM 617914); autistic features were reported in both affected siblings from one of four families with this disorder in Makrythanasis et al., 2018.

Score Delta: Score remained at 3

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo missense variant in the KIF14 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KIF14 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 3 CNVs from SCZ cases (5 total) vs. 0 CNVs in controls (Odds ratio 6.55, P = 1.0E-05)]. Biallelic mutations in this gene are responsible for an autosomal recessive form of microcephaly (autosomal recessive primary microcephaly-20 or MCPH20; OMIM 617914); autistic features were reported in both affected siblings from one of four families with this disorder in Makrythanasis et al., 2018.

Reports Added
[New Scoring Scheme]
10/1/2018
icon
3

Increased from to 3

Description

A de novo missense variant in the KIF14 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KIF14 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 3 CNVs from SCZ cases (5 total) vs. 0 CNVs in controls (Odds ratio 6.55, P = 1.0E-05)]. Biallelic mutations in this gene are responsible for an autosomal recessive form of microcephaly (autosomal recessive primary microcephaly-20 or MCPH20; OMIM 617914); autistic features were reported in both affected siblings from one of four families with this disorder in Makrythanasis et al., 2018.

Krishnan Probability Score

Score 0.12457326773964

Ranking 25730/25841 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 6.0274856650418E-5

Ranking 13367/18225 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
Sanders TADA Score

Score 0.9423180256482

Ranking 15261/18665 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).
Zhang D Score

Score -0.055586043494784

Ranking 10620/20870 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.
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