Human Gene Module / Chromosome 15 / MEIS2

MEIS2Meis homeobox 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
4 / 13
Rare Variants / Common Variants
29 / 0
EAGLE Score
7.5
Moderate Learn More
Aliases
MEIS2, CPCMR,  HsT18361,  MRG1
Associated Syndromes
-
Chromosome Band
15q14
Associated Disorders
ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Heterozygous mutations in the MEIS2 gene, frequently in the form of 15q14 microdeletions, are responsible for cleft palate, cardiac defects, and mental retardation (CPCMR; OMIM 600987). A de novo in-frame deletion variant in the MEIS2 gene was identified in a female patient diagnosed with ASD in Louw et al., 2015. A de novo 15q14 microdeletion involving MEIS2 was observed in a patient presenting with autistic behavior in Shimojima et al., 2017. Douglas et al., 2018 reported four individuals with de novo predicted damaging missense variants in the MEIS2 gene; in addition to features resembling those observed in patients with 15q14 deletions, three of the individuals in Douglas et al., 2018 presented with autism or ASD.

Molecular Function

This gene encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. TALE homeobox proteins are highly conserved transcription regulators, and several members have been shown to be essential contributors to developmental programs.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MEIS2 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary MEIS2 involvement in cardiac development, cleft palate, and intellectual disability Louw JJ , et al. (2015) No ASD
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support A 15q14 microdeletion involving MEIS2 identified in a patient with autism spectrum disorder Shimojima K , et al. (2017) No Autistic behavior
4 Recent Recommendation De novo missense variants in MEIS2 recapitulate the microdeletion phenotype of cardiac and palate abnormalities, developmental delay, intellectual disability and dysmorphic features Douglas G , et al. (2018) No ASD
5 Support Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability Verheije R , et al. (2018) No ASD
6 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders Schluth-Bolard C , et al. (2019) No Microcephaly
7 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
8 Support - Hildebrand MS et al. (2020) No ASD, DD
9 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
10 Support - Mojarad BA et al. (2021) No ID
11 Support - Carvalho LML et al. (2022) No -
12 Support - Zhou X et al. (2022) Yes -
13 Support - et al. () No -
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1021C>T p.Gln341Ter stop_gained De novo - - 38321498 et al. ()
- - copy_number_loss De novo - - 30291340 Verheije R , et al. (2018)
- - copy_number_loss Unknown - - 30291340 Verheije R , et al. (2018)
- - copy_number_loss De novo - - 28736618 Shimojima K , et al. (2017)
- - translocation De novo - - 30923172 Schluth-Bolard C , et al. (2019)
- - copy_number_loss De novo - Simplex 35597848 Carvalho LML et al. (2022)
c.520C>T p.Arg174Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
- - copy_number_loss Unknown Not maternal - 30291340 Verheije R , et al. (2018)
c.639+1G>A - splice_site_variant De novo - - 30291340 Verheije R , et al. (2018)
c.640-2A>G - splice_site_variant De novo - - 30291340 Verheije R , et al. (2018)
c.978-2A>G - splice_site_variant De novo - - 30291340 Verheije R , et al. (2018)
c.829C>T p.Gln277Ter stop_gained De novo - - 30291340 Verheije R , et al. (2018)
c.978G>A p.Trp326Ter stop_gained De novo - - 30291340 Verheije R , et al. (2018)
c.520C>T p.Arg174Ter stop_gained De novo - - 31452935 Feliciano P et al. (2019)
c.5-2A>G - splice_site_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1323C>T p.His441%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.905C>T p.Pro302Leu missense_variant De novo - - 30055086 Douglas G , et al. (2018)
c.965A>T p.Gln322Leu missense_variant De novo - - 30055086 Douglas G , et al. (2018)
c.992G>A p.Arg331Lys missense_variant De novo - - 30055086 Douglas G , et al. (2018)
c.1004T>C p.Val335Ala missense_variant De novo - - 30055086 Douglas G , et al. (2018)
c.998G>A p.Arg333Lys missense_variant De novo - - 30291340 Verheije R , et al. (2018)
c.324_326del p.Ala109del inframe_deletion De novo - - 25712757 Louw JJ , et al. (2015)
c.973A>C p.Asn325His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1099C>T p.Gln367Ter stop_gained Unknown - Simplex 33526774 Mojarad BA et al. (2021)
c.956C>T p.Thr319Ile missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.383del p.Lys128SerfsTer19 frameshift_variant De novo - - 30291340 Verheije R , et al. (2018)
c.868dup p.Ile290AsnfsTer40 frameshift_variant De novo - - 30291340 Verheije R , et al. (2018)
c.934_937del p.Leu312ArgfsTer11 frameshift_variant De novo - - 30291340 Verheije R , et al. (2018)
c.934_937del p.Leu312ArgfsTer11 frameshift_variant Unknown - Unknown 32345733 Hildebrand MS et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
1
icon
1

Score remained at 1

Description

Heterozygous mutations in the MEIS2 gene, frequently in the form of 15q14 microdeletions, are responsible for cleft palate, cardiac defects, and mental retardation (CPCMR; OMIM 600987). A de novo in-frame deletion variant in the MEIS2 gene was identified in a female patient diagnosed with ASD in Louw et al., 2015. A de novo 15q14 microdeletion involving MEIS2 was observed in a patient presenting with autistic behavior in Shimojima et al., 2017. Douglas et al., 2018 reported four individuals with de novo predicted damaging missense variants in the MEIS2 gene; in addition to features resembling those observed in patients with 15q14 deletions, three of the individuals in Douglas et al., 2018 presented with autism or ASD. Verheije et al., 2018 collected 23 previously reported individuals with either a de novo sequence variant in MEIS2 (9 patients) or a 15q14 microdeletion affecting MEIS2 (14 patients) and determined that autism was observed in 2/9 patients with a de novo MEIS2 sequence variants and in 3/14 patients with a 15q14 microdeletion affecting MEIS2.

Reports Added
[Genome sequencing broadens the range of contributing variants with clinical implications in schizophrenia2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Heterozygous mutations in the MEIS2 gene, frequently in the form of 15q14 microdeletions, are responsible for cleft palate, cardiac defects, and mental retardation (CPCMR; OMIM 600987). A de novo in-frame deletion variant in the MEIS2 gene was identified in a female patient diagnosed with ASD in Louw et al., 2015. A de novo 15q14 microdeletion involving MEIS2 was observed in a patient presenting with autistic behavior in Shimojima et al., 2017. Douglas et al., 2018 reported four individuals with de novo predicted damaging missense variants in the MEIS2 gene; in addition to features resembling those observed in patients with 15q14 deletions, three of the individuals in Douglas et al., 2018 presented with autism or ASD. Verheije et al., 2018 collected 23 previously reported individuals with either a de novo sequence variant in MEIS2 (9 patients) or a 15q14 microdeletion affecting MEIS2 (14 patients) and determined that autism was observed in 2/9 patients with a de novo MEIS2 sequence variants and in 3/14 patients with a 15q14 microdeletion affecting MEIS2.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Heterozygous mutations in the MEIS2 gene, frequently in the form of 15q14 microdeletions, are responsible for cleft palate, cardiac defects, and mental retardation (CPCMR; OMIM 600987). A de novo in-frame deletion variant in the MEIS2 gene was identified in a female patient diagnosed with ASD in Louw et al., 2015. A de novo 15q14 microdeletion involving MEIS2 was observed in a patient presenting with autistic behavior in Shimojima et al., 2017. Douglas et al., 2018 reported four individuals with de novo predicted damaging missense variants in the MEIS2 gene; in addition to features resembling those observed in patients with 15q14 deletions, three of the individuals in Douglas et al., 2018 presented with autism or ASD. Verheije et al., 2018 collected 23 previously reported individuals with either a de novo sequence variant in MEIS2 (9 patients) or a 15q14 microdeletion affecting MEIS2 (14 patients) and determined that autism was observed in 2/9 patients with a de novo MEIS2 sequence variants and in 3/14 patients with a 15q14 microdeletion affecting MEIS2.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
4/1/2019
S
icon
S

Increased from S to S

Description

Heterozygous mutations in the MEIS2 gene, frequently in the form of 15q14 microdeletions, are responsible for cleft palate, cardiac defects, and mental retardation (CPCMR; OMIM 600987). A de novo in-frame deletion variant in the MEIS2 gene was identified in a female patient diagnosed with ASD in Louw et al., 2015. A de novo 15q14 microdeletion involving MEIS2 was observed in a patient presenting with autistic behavior in Shimojima et al., 2017. Douglas et al., 2018 reported four individuals with de novo predicted damaging missense variants in the MEIS2 gene; in addition to features resembling those observed in patients with 15q14 deletions, three of the individuals in Douglas et al., 2018 presented with autism or ASD. Verheije et al., 2018 collected 23 previously reported individuals with either a de novo sequence variant in MEIS2 (9 patients) or a 15q14 microdeletion affecting MEIS2 (14 patients) and determined that autism was observed in 2/9 patients with a de novo MEIS2 sequence variants and in 3/14 patients with a 15q14 microdeletion affecting MEIS2.

Reports Added
[Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...2019]
10/1/2018
S
icon
S

Increased from S to S

Description

Heterozygous mutations in the MEIS2 gene, frequently in the form of 15q14 microdeletions, are responsible for cleft palate, cardiac defects, and mental retardation (CPCMR; OMIM 600987). A de novo in-frame deletion variant in the MEIS2 gene was identified in a female patient diagnosed with ASD in Louw et al., 2015. A de novo 15q14 microdeletion involving MEIS2 was observed in a patient presenting with autistic behavior in Shimojima et al., 2017. Douglas et al., 2018 reported four individuals with de novo predicted damaging missense variants in the MEIS2 gene; in addition to features resembling those observed in patients with 15q14 deletions, three of the individuals in Douglas et al., 2018 presented with autism or ASD. Verheije et al., 2018 collected 23 previously reported individuals with either a de novo sequence variant in MEIS2 (9 patients) or a 15q14 microdeletion affecting MEIS2 (14 patients) and determined that autism was observed in 2/9 patients with a de novo MEIS2 sequence variants and in 3/14 patients with a 15q14 microdeletion affecting MEIS2.

Reports Added
[Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability.2018]
Krishnan Probability Score

Score 0.54359785644328

Ranking 1420/25841 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 0.99425495510655

Ranking 1586/18225 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 0.93499763783444

Ranking 12740/18665 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 0.083167833905367

Ranking 6472/20870 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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