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Intellectual disability

Gene: MEIS2

Green List (high evidence)

MEIS2 (Meis homeobox 2)
EnsemblGeneIds (GRCh38): ENSG00000134138
EnsemblGeneIds (GRCh37): ENSG00000134138
OMIM: 601740, Gene2Phenotype
MEIS2 is in 2 panels

3 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: Promoted from red to green based on the additional evidence provided by Konstantinos Varvagiannis, which shows that there are enough cases to support gene-disease association. MEIS2 is associated with a phenotype in OMIM but not in Gene2Phenotype.
Created: 18 Feb 2019, 4:17 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 30291340 is a collaborative study on 23 previously unreported individuals with de novo mutations in MEIS2 (9 subjects) or deletions encompassing MEIS14 (14 subjects). The authors review the previously published cases with relevant mutations or CNVs.

The 9 de novo variants included 2 stopgain SNVs, 3 frameshift variants, 3 splice variants and a missense SNV affecting the MEIS2 homedomain. These de novo variants add to 2 previously published patients with loss-of-function mutations (PMID: 25712757, 27225850).

Deletions in the 14 patients had variable sizes (3.1 Mb mean) although the authors review 11 previously published individuals (from several publications), 2 of whom had an intragenic MEIS2 microdeletion and 1 an intragenic microduplication.

A similar phenotype was observed in subjects with mutation or CNVs and included palatal defects, congenital heart defects and intellectual disability. There was no distinct/recognizable facial gestalt although a few features appeared to be more common (eg. bitemporal narrowing, arched eyebrows, hypoplastic alae nasi, thin upper lip). Patients with CNVs had variable degree of intellectual disability and features depending on other affected genes (eg. CAL spots due to involvement of SPRED1).

Altogether, loss-of-function appears to be the mechanism (MEIS2 has a pLI of 0.99). A dominant negative effect is also proposed for the missense variant since the specific individual appeared to be more severely affected (although he presented also with other rare variants). In ExAC, MEIS2 has a missense constraint score of 3.2. //

PMID: 30055086 describes 4 individuals, all harboring de novo missense variants in MEIS2. All the variants reported are located within the homedomain (residues 276-338). The phenotype is consistent with what is described in the aforementioned publication, although possibly more severe (incl. failure to thrive, gastrointestinal issues, skeletal and other abnormalities). Based on this, the authors of this article propose - again - a dominant negative effect for missense variants. //

MEIS2 is included in intellectual disability gene panels offered by different diagnostic laboratories. //

Based on the additional publications this gene should probably be upgraded to green as previously suggested.
Created: 13 Oct 2018, 11:06 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Oral cleft; Abnormal heart morphology; Intellectual disability

Publications

Variants in this GENE are reported as part of current diagnostic practice

Zornitza Stark (Australian Genomics)

Green List (high evidence)

At least 3 individuals from unrelated families reported with de novo variants in this gene, ID is part of the phenotype.
Created: 22 Jun 2018, 11:53 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cleft palate, cardiac defects, and mental retardation

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Cleft palate, cardiac defects, and mental retardation
  • Oral cleft
  • Abnormal heart morphology
  • Intellectual disability
  • Cleft palate, cardiac defects, and mental retardation, 600987
OMIM
601740
Clinvar variants
Variants in MEIS2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

18 Feb 2019, Gel status: 3

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MEIS2 were set to 27225850, 24678003, 25712757; 30291340; 30055086

18 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: meis2 has been classified as Green List (High Evidence).

18 Feb 2019, Gel status: 1

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation to Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987

18 Feb 2019, Gel status: 1

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MEIS2 were set to 27225850, 24678003, 25712757

29 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to MEIS2.

22 Jun 2018, Gel status: 0

Added New Source

Zornitza Stark (Australian Genomics)

MEIS2 was added to Intellectual disability panel. Sources: Literature

22 Jun 2018, Gel status: 0

Created

Zornitza Stark (Australian Genomics)

MEIS2 was created by Zornitza Stark