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Intellectual disability

Gene: MED12

Green List (high evidence)

MED12 (mediator complex subunit 12)
EnsemblGeneIds (GRCh38): ENSG00000184634
EnsemblGeneIds (GRCh37): ENSG00000184634
OMIM: 300188, Gene2Phenotype
MED12 is in 14 panels

4 reviews

Eleanor Williams (Genomics England Curator)

Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+) female cases reported now with de novo variants in MED12 and an intellectual disability phenotype so consideration should be given to changing the mode of inheritance to monoallelic in females.
Created: 30 Sep 2021, 12:43 p.m. | Last Modified: 30 Sep 2021, 12:43 p.m.
Panel Version: 3.1315
PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 7 individuals with truncating variants had a syndromic presentation with variable ID, short stature, facial dysmorphism, feeding difficulties and skeletal abnormalities. 11 individuals with missense variants are reported to have a phenotype of severe ID, autistic features and limited speech, and variable dysmorphic features. 11/18 have severe intellectual disability.

Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case.

Note: Li et al 2021 (PMID: 33244166) report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing but intellectual disability is not a feature of this syndrome.
Created: 30 Sep 2021, 12:35 p.m. | Last Modified: 30 Sep 2021, 12:35 p.m.
Panel Version: 3.1313

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Publications

Caroline Wright (Sanger)

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
OPITZ-KAVEGGIA SYNDROME (OKS)

Publications

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known;in_UKGTN_v12 . Main mutation mechanism : Uncertain
Created: 27 Jul 2017, 7:28 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; find_uk10k; gilissen_2014_known; sfari_20150206; UKGTN_v12; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_green_20160217; neuro_20160418_strict; Uncertain. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 12:49 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

Lu Raymond (university of cambridge )

Green List (high evidence)

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
Phenotypes
  • Opitz-Kaveggia syndrome, 305450
  • Lujan-Fryns syndrome, 309520
  • Ohdo syndrome, X-linked, 300895
  • OPITZ-KAVEGGIA SYNDROME (OKS)
Tags
Skewed X-inactivation Q3_21_MOI Q3_21_expert_review
OMIM
300188
Clinvar variants
Variants in MED12
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Sep 2021, Gel status: 3

Added Tag, Added Tag, Added Tag

Eleanor Williams (Genomics England Curator)

Tag Skewed X-inactivation tag was added to gene: MED12. Tag Q3_21_MOI tag was added to gene: MED12. Tag Q3_21_expert_review tag was added to gene: MED12.

30 Sep 2021, Gel status: 3

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females

30 Sep 2021, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: MED12 were set to 6711603

29 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to MED12.

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

2 May 2017, Gel status: 4

Set publications

Louise Daugherty (Genomics England Curator)

Publications for MED12 were set to 6711603

2 May 2017, Gel status: 4

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for MED12 were set to Opitz-Kaveggia syndrome, 305450; Lujan-Fryns syndrome, 309520; Ohdo syndrome, X-linked, 300895; OPITZ-KAVEGGIA SYNDROME (OKS)

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

MED12 was added to Intellectual disabilitypanel. Source: Expert Review Green Model of inheritance for gene MED12 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene MED12 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

MED12 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

MED12 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen