Human Gene Module / Chromosome 11 / MARK2

MARK2microtubule affinity regulating kinase 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 7
Rare Variants / Common Variants
49 / 0
EAGLE Score
20.05
Strong Learn More
Aliases
-
Associated Syndromes
-
Chromosome Band
11q13.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Functional
Relevance to Autism

A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases for the SPARK cohort, in Zhou et al., 2022 identified MARK2 as a gene reaching exome-wide significance (P < 2.5E-06); association of MARK2 with ASD risk was primarily driven by de novo variants. A de novo missense variant in MARK2 was also identified in an ASD proband from the SAGE cohort in Guo et al., 2019. More recently, Gong et al., 2024 reported 31 individuals with MARK2 variants presenting with autism spectrum disorder (30/31, 96.8%), developmental delay/intellectual disability (29/29, 100%), speech/language problems (31/31, 100%), additional behavioral abnormalities (20/27, 74.1%), and distinctive recurrent facial features including a narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears. Moreover, Gong et al., 2024 demonstrated that MARK2 loss in either proband-derived or CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) led to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs), while Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behavior.

Molecular Function

This gene encodes a member of the Par-1 family of serine/threonine protein kinases. The protein is an important regulator of cell polarity in epithelial and neuronal cells, and also controls the stability of microtubules through phosphorylation and inactivation of several microtubule-associating proteins. The protein localizes to cell membranes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MARK2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
4 Primary - Zhou X et al. (2022) Yes -
5 Support - Chen WX et al. (2022) Yes -
6 Recent Recommendation - Maolei Gong et al. (2024) Yes DD, ID, epilepsy/seizures
7 Support - Hanna O Caiola et al. (2024) Yes Epilepsy/seizures
Rare Variants   (49)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.211C>T p.Arg71Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.404-2A>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.457C>T p.Arg153Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1934+1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1416+8G>C - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.211C>T p.Arg71Ter stop_gained Unknown - - 39419027 Maolei Gong et al. (2024)
c.403G>A p.Gly135Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.691G>A p.Val231Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2029G>A p.Gly677Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2239C>T p.Gln747Ter stop_gained De novo - - 39419027 Maolei Gong et al. (2024)
c.1514+2T>G p.? splice_site_variant Unknown - - 39419027 Maolei Gong et al. (2024)
c.1934+1G>A p.? splice_site_variant Unknown - - 39419027 Maolei Gong et al. (2024)
c.688G>T p.Glu230Ter stop_gained Familial Maternal - 35982159 Zhou X et al. (2022)
c.1807C>T p.Arg603Ter stop_gained Familial Paternal - 35982159 Zhou X et al. (2022)
c.500A>C p.His167Pro missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1677-1G>C - splice_site_variant Unknown Not paternal - 35982159 Zhou X et al. (2022)
c.757C>T p.Gln253Ter stop_gained De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.904C>T p.Arg302Ter stop_gained De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.2029G>A p.Gly677Ser missense_variant De novo - Unknown 30504930 Guo H , et al. (2018)
c.1750C>T p.Arg584Ter stop_gained De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.2239C>T p.Gln747Ter stop_gained De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.904C>T p.Arg302Ter stop_gained Familial Paternal - 39419027 Maolei Gong et al. (2024)
c.337+1G>T p.? splice_site_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.989-1G>A p.? splice_site_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1990C>T p.Arg664Ter stop_gained Familial Paternal - 39419027 Maolei Gong et al. (2024)
c.1101+1G>A p.? splice_site_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.235-2A>G p.? splice_site_variant Familial Paternal - 39419027 Maolei Gong et al. (2024)
c.239C>T p.Ala80Val missense_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.289C>T p.Leu97%3D synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.403G>A p.Gly135Arg missense_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.581T>C p.Phe194Ser missense_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.905G>A p.Arg302Gln missense_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.2255T>C p.Val752Ala missense_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.2291G>C p.Arg764Pro missense_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.699del p.Trp234GlyfsTer3 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.179del p.Gly60AlafsTer8 frameshift_variant Familial Paternal - 35982159 Zhou X et al. (2022)
c.258_259dup p.Thr87ArgfsTer4 frameshift_variant Unknown - - 39419027 Maolei Gong et al. (2024)
c.1002del p.Met335TrpfsTer20 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1426del p.Leu476SerfsTer31 frameshift_variant De novo - Simplex 36320054 Chen WX et al. (2022)
c.288dupA p.Leu97ThrfsTer18 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.812delT p.Phe271SerfsTer25 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1120delA p.Thr374ProfsTer2 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1181dupA p.Val395GlyfsTer27 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1769delG p.Gly590ValfsTer26 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1516dupC p.Leu506ProfsTer47 frameshift_variant Unknown Not maternal - 39419027 Maolei Gong et al. (2024)
c.2168_2169delGC p.Cys723SerfsTer6 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1888_1889insG p. Ala630GlyfsTer29 frameshift_variant De novo - Simplex 39419027 Maolei Gong et al. (2024)
c.1938_1939delTC p.Leu647ValfsTer11 frameshift_variant Familial Paternal - 39419027 Maolei Gong et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

10/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.49389099424661

Ranking 3933/25841 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 0.99990085465415

Ranking 679/18225 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 0.66496167398313

Ranking 964/18665 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 0.46955795700168

Ranking 752/20870 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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