Intellectual disability - microarray and sequencing
Gene: MED12The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.
Panel Version: 3.1519
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
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
OPITZ-KAVEGGIA SYNDROME (OKS)
Publications
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 : UncertainCreated: 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 TrustCreated: 19 Jul 2017, 12:49 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications
Tag Q3_21_MOI was removed from gene: MED12. Tag Q3_21_expert_review was removed from gene: MED12.
Source NHS GMS was added to MED12. 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, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
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.
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
Publications for gene: MED12 were set to 6711603
Source Victorian Clinical Genetics Services was added to MED12.
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.
Publications for MED12 were set to 6711603
Phenotypes for MED12 were set to Opitz-Kaveggia syndrome, 305450; Lujan-Fryns syndrome, 309520; Ohdo syndrome, X-linked, 300895; OPITZ-KAVEGGIA SYNDROME (OKS)
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
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
Model of inheritance for gene MED12 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females
MED12 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen
MED12 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen