Intellectual disability
Gene: MED12L

MED12L (mediator complex subunit 12 like)
EnsemblGeneIds (GRCh38): ENSG00000144893
EnsemblGeneIds (GRCh37): ENSG00000144893
OMIM: 611318, Gene2Phenotype
MED12L is in 1 panel

2 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is now sufficient evidence for this gene to be promoted to green following GMS review.
Created: 21 Oct 2025, 10:12 p.m. | Last Modified: 21 Oct 2025, 10:12 p.m.

Panel Version: 9.144

Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030 (last curated November 19th, 2024)

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.
Created: 21 Oct 2025, 10:09 p.m. | Last Modified: 21 Oct 2025, 10:14 p.m.

Panel Version: 9.144

Comment on list classification: Rating Amber. CNVs encompass other genes. Two cases with SNVs have moderate/severe ID and one of these also has a VUS in TUBB2B. The other two SNV cases have mild ID.
Created: 19 Jun 2019, 10:40 a.m.

Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 31155615 - Nizon et al. 2019 - 7 affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing. All affected individuals presented with intellectual disability and/or developmental delay (3 mild, 3 moderate, 1 severe with seizures). 3 individuals had a MED12L deletion or duplication. All encompass other genes aswell as MED12L. In 2 cases these could be confirmed as de novo. 4 individuals had single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). In two cases these variants were found to have occurred de novo. One individual also had a variant in TUBB2B that was classified as unknown signficance. Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals (Konstantios Varvagiannis notes this data is from individuals with CNVs).

Summary: 7 unrelated cases, 4 different SNVs plus 3 CNVs. Mild ID in 2 of the SNV cases and 1 CNV case. Some segregation and functional data.
Created: 19 Jun 2019, 10:31 a.m.

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

Phenotypes
Nizon-Isidor syndrome, OMIM:618872; Nizon-Isidor syndrome, MONDO:0030030

Publications

Created: 19 Jun 2019, 10:30 a.m.
Last Modified: 21 Oct 2025, 10:14 p.m.
Panel version: 9.141

Konstantinos Varvagiannis (Other)

I don't know

Nizon et al. (2019 - PMID: 31155615) report on 7 unrelated individuals with nucleotide or copy-number variants in MED12L.

Features included motor delay (4/7), speech impairment (7/7) with ID of variable degrees (7/7 - mild to severe). Variable behavioral abnormalities (ASD in 4/7, aggressive behavior, ADHD, etc), functional GI anomalies, corpus callosum abnormalities and seizures were among other features noted in some/few. There was no recognizable facial phenotype.

Nucleotide variants included 1 stopgain, 1 frameshift and 2 splice site variants. 3 CNVs were reported (two 3q25.1 microduplications of 460- and 147-kb respectively and one microdeletion of 291-kb) although all spanned also other genes.

De novo occurrence was shown for 2 CNVs and 2 SNVs, as parental samples were unavailable for 3 of the subjects.

Contribution of other genetic (eg. an inherited 22q11.2 microduplication, VUS in other genes) or environmental factors could not be ruled out for few individuals.

Among the arguments provided:

MED12L encodes a subunit of the kinase module of the mediator complex, a complex required for transcription by RNA polymerase II. Mutations in other subunits of the kinase module (eg. MED12, MED13L, etc) have been implicated in intellectual disability.

The protein is localized in the nucleus. The gene is mainly expressed in the brain.

The functional effect of 2 CNVs was evaluated using the recovery of RNA synthesis assay, an assay reflecting global transcriptional activity. Fibrobast studies from one individual with microdeletion and one further subject with microduplication demonstrated decreased RNA synthesis compared to controls. Decreased RNA synthesis was also observed in cell lines from individuals with mutations in other genes for subunits of the mediator complex (eg. MED12 or MED13L) or from individuals with Cockayne syndrome.

Therefore haploinsufficiency is suggested to underly the transcriptional defect. (MED12L also appears to be intolerant to LoF variation with a pLI score of 1).

Some features appear to be common among the disorders caused by pathogenic variants in MED12L or other subunits of the kinase module (MED12, MED13, MED13L) eg. ID, abnormal behaviour or autistic features.

Animal models are not discussed / (probably not) available (MGI for Med12l : http://www.informatics.jax.org/marker/MGI:2139916)

MED12L is not associated with any phenotype in OMIM or G2P. The gene is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID panel, probably as amber (4 variants affecting only MED12L, segregation studies performed for 2, degree of ID reported mild on 2 occasions) pending further reports.
Sources: Literature
Created: 8 Jun 2019, 5:33 p.m.

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

Phenotypes
Motor delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Abnormality of the abdomen; Seizures; Abnormality of the corpus callosum

Publications

31155615

Created: 8 Jun 2019, 5:33 p.m.

Panel version: 2.857

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Amber

Phenotypes

Nizon-Isidor syndrome, OMIM:618872
Nizon-Isidor syndrome, MONDO:0030030

Tags

Q3_25_promote_green

OMIM

611318

Clinvar variants

Variants in MED12L

Penetrance

unknown

Publications

Panels with this gene

Intellectual disability