MCPH1microcephalin 1
Autism Reports / Total Reports
12 / 19Rare Variants / Common Variants
21 / 0Aliases
MCPH1, MCT, BRIT1, FLJ12847Associated Syndromes
-Chromosome Band
8p23.1Associated Disorders
-Relevance to Autism
Studies have found rare variants in the MCPH1 gene that are associated with autism (e.g. Ozgen et al., 2009; Neale et al., 2012).
Molecular Function
This protein is implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.
External Links
SFARI Genomic Platforms
Reports related to MCPH1 (19 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | Identification of microcephalin, a protein implicated in determining the size of the human brain | Jackson AP , et al. (2002) | No | - |
| 2 | Highly Cited | Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans | Evans PD , et al. (2005) | No | - |
| 3 | Support | Transmitted duplication of 8p23.1-8p23.2 associated with speech delay, autism and learning difficulties | Glancy M , et al. (2008) | Yes | - |
| 4 | Recent Recommendation | Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1 | Tibelius A , et al. (2009) | No | - |
| 5 | Primary | Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders | Ozgen HM , et al. (2009) | Yes | - |
| 6 | Recent Recommendation | A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation | Richards MW , et al. (2009) | No | - |
| 7 | Support | Social Responsiveness Scale-aided analysis of the clinical impact of copy number variations in autism | van Daalen E , et al. (2011) | Yes | - |
| 8 | Recent Recommendation | Molecular basis for the association of microcephalin (MCPH1) protein with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex | Singh N , et al. (2011) | No | - |
| 9 | Support | Patterns and rates of exonic de novo mutations in autism spectrum disorders | Neale BM , et al. (2012) | Yes | - |
| 10 | Support | A discovery resource of rare copy number variations in individuals with autism spectrum disorder | Prasad A , et al. (2013) | Yes | - |
| 11 | Support | Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder | Girirajan S , et al. (2013) | Yes | - |
| 12 | Support | Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families | Alazami AM , et al. (2015) | No | - |
| 13 | Recent Recommendation | De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia | Takata A , et al. (2016) | No | - |
| 14 | Support | Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder | Lim ET , et al. (2017) | Yes | - |
| 15 | Support | Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders | Li J , et al. (2017) | Yes | - |
| 16 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
| 17 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
| 18 | Support | - | Zhou X et al. (2022) | Yes | - |
| 19 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
Rare Variants (21)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | copy_number_loss | De novo | - | - | 19793310 | Ozgen HM , et al. (2009) | |
| - | - | complex_structural_alteration | - | - | - | 19793310 | Ozgen HM , et al. (2009) | |
| - | - | copy_number_loss | Unknown | - | Unknown | 23275889 | Prasad A , et al. (2013) | |
| - | - | copy_number_loss | De novo | - | Simplex | 21837366 | van Daalen E , et al. (2011) | |
| - | - | copy_number_gain | Familial | Maternal | Simplex | 18716609 | Glancy M , et al. (2008) | |
| - | - | copy_number_gain | Familial | Maternal | Multiplex | 19793310 | Ozgen HM , et al. (2009) | |
| c.1651G>T | p.Glu551Ter | stop_gained | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| - | - | copy_number_gain | Familial | Maternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| - | - | copy_number_gain | Familial | Paternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| - | - | copy_number_loss | Familial | Maternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| c.2078G>A | p.Arg693His | missense_variant | Familial | - | Simplex | 28831199 | Li J , et al. (2017) | |
| c.2445G>C | p.Trp815Cys | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.974C>T | p.Thr325Met | missense_variant | De novo | - | Simplex | 28714951 | Lim ET , et al. (2017) | |
| - | - | copy_number_loss | Familial | Both parents | Multiplex | 25558065 | Alazami AM , et al. (2015) | |
| c.322C>T | p.Arg108Cys | missense_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| c.2484T>A | p.Pro828= | synonymous_variant | De novo | - | Simplex | 22495311 | Neale BM , et al. (2012) | |
| c.1826-1G>C | - | splice_site_variant | Familial | Maternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.2445G>A | p.Trp815Ter | stop_gained | Familial | Paternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.322-1G>C | - | splice_site_variant | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.1561G>T | p.Glu521Ter | stop_gained | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.2145G>A | p.Trp715Ter | stop_gained | Familial | Paternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) |
Common Variants
No common variants reported.
SFARI Gene score
2
Strong Candidate
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe 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
2
Decreased from 3 to 2
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
10/1/2019
4
3
Decreased from 4 to 3
New Scoring Scheme
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
Reports Added
[New Scoring Scheme]7/1/2019
4
4
Decreased from 4 to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
10/1/2017
4
4
Decreased from 4 to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
7/1/2017
4
4
Decreased from 4 to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
4/1/2016
4
4
Decreased from 4 to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
Reports Added
[Transmitted duplication of 8p23.1-8p23.2 associated with speech delay, autism and learning difficulties.2008] [Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders.2009] [Social Responsiveness Scale-aided analysis of the clinical impact of copy number variations in autism.2011] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.2015] [Identification of microcephalin, a protein implicated in determining the size of the human brain.2002] [Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.2005] [Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1.2009] [A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.2009] [Molecular basis for the association of microcephalin (MCPH1) protein with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promot...2011] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]1/1/2015
4
4
Decreased from 4 to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
7/1/2014
No data
4
Increased from No data to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
4/1/2014
No data
4
Increased from No data to 4
Description
Gene has multiple putative mutations identified (Ozgen et al., 2009; Glancy et al., 2009), yet they have not been studied in statistically convincing case-control examination.
Krishnan Probability Score
Score 0.41294697282543
Ranking 21967/25841 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 5.1650703068718E-18
Ranking 17877/18225 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 0.92846338633848
Ranking 10921/18665 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 1
Ranking 426/461 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 0.12046437981611
Ranking 5719/20870 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 MCPH1(1 CNVs)
Sort By:
| 8p23.1 | 49 | Deletion-Duplication | 72 / 445 |