Human Gene Module / Chromosome 4 / CEP135

CEP135centrosomal protein 135

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
23 / 0
Aliases
CEP135, CEP4,  KIAA0635,  MCPH8
Associated Syndromes
-
Chromosome Band
4q12
Associated Disorders
-
Relevance to Autism

Two de novo damaging missense variants in the CEP135 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were detected in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CEP135 as an ASD candidate gene with a PTADA of 0.006635.

Molecular Function

This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Homozygous mutations in this gene are associated with autosomal recessive primary microcephaly-8 (MCPH8; OMIM 614673), a disorder characterized by severe intellectual disability and unintelligible speech (Hussain et al., 2012; Farooq et al., 2016).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CEP135 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function Hussain MS , et al. (2012) No -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Support A novel splice site mutation in CEP135 is associated with primary microcephaly in a Pakistani family Farooq M , et al. (2015) No -
6 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2764C>T p.Arg922Ter stop_gained Familial - - 28831199 Li J , et al. (2017)
c.1622A>G p.Asn541Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2839T>C p.Ser947Pro missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
G>A p.Glu923Lys missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
G>A p.Glu923Lys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2722C>T p.Arg908Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.65G>T p.Arg22Leu missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.142C>T p.Arg48Trp missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.143G>A p.Arg48Gln missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.203T>C p.Leu68Ser missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.509G>A p.Arg170His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.593T>G p.Leu198Arg missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.638T>C p.Val213Ala missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.850A>C p.Asn284His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1000G>A p.Glu334Lys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1010T>C p.Leu337Pro missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1325G>A p.Arg442His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1360C>G p.Arg454Gly missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2398G>C p.Asp800His missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2767G>A p.Glu923Lys missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2767G>A p.Glu923Lys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.3326G>A p.Arg1109Gln missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2056C>T p.Arg686Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo damaging missense variants in the CEP135 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were detected in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CEP135 as an ASD candidate gene with a PTADA of 0.006635. Homozygous mutations in this gene are associated with autosomal recessive primary microcephaly-8 (MCPH8; OMIM 614673), a disorder characterized by severe intellectual disability and unintelligible speech (Hussain et al., 2012; Farooq et al., 2016).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo damaging missense variants in the CEP135 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were detected in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CEP135 as an ASD candidate gene with a PTADA of 0.006635. Homozygous mutations in this gene are associated with autosomal recessive primary microcephaly-8 (MCPH8; OMIM 614673), a disorder characterized by severe intellectual disability and unintelligible speech (Hussain et al., 2012; Farooq et al., 2016).

Reports Added
[New Scoring Scheme]
7/1/2017
icon
3

Increased from to 3

Description

Two de novo damaging missense variants in the CEP135 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were detected in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CEP135 as an ASD candidate gene with a PTADA of 0.006635. Homozygous mutations in this gene are associated with autosomal recessive primary microcephaly-8 (MCPH8; OMIM 614673), a disorder characterized by severe intellectual disability and unintelligible speech (Hussain et al., 2012; Farooq et al., 2016).

Krishnan Probability Score

Score 0.44703549644959

Ranking 14173/25841 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 4.8541134370725E-17

Ranking 17821/18225 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 0.86909208137611

Ranking 4258/18665 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 -0.12227544296241

Ranking 13216/20870 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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