Intellectual disability - microarray and sequencing
Gene: MEIS2 Green List (high evidence)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.
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
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
Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987 to Cleft palate, cardiac defects, and mental retardation, OMIM:600987; Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies, MONDO:0010970
Publications for gene: MEIS2 were set to 27225850, 24678003, 25712757; 30291340; 30055086
Gene: meis2 has been classified as Green List (High Evidence).
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
Publications for gene: MEIS2 were set to 27225850, 24678003, 25712757
Source Victorian Clinical Genetics Services was added to MEIS2.
MEIS2 was added to Intellectual disability panel. Sources: Literature
MEIS2 was created by Zornitza Stark
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.