Clefting
Gene: MED12
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 5:13 p.m. | Last Modified: 1 Feb 2023, 5:13 p.m.
Panel Version: 3.5
The mode of inheritance has been left as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' with agreement from the Genomics Unit at NHSE.Created: 8 Feb 2023, 3:34 p.m. | Last Modified: 8 Feb 2023, 3:34 p.m.
Panel Version: 3.6
Comment on mode of inheritance: X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.Created: 28 Sep 2021, 10:53 a.m. | Last Modified: 28 Sep 2021, 10:53 a.m.
Panel Version: 2.50
Comment on list classification: Promoting this gene from red to amber with the recommendation of a green rating following GMS review. There are 7 reported cases with cleft lip/palate and a variant identified in MED12.Created: 21 Jul 2021, 3:40 p.m. | Last Modified: 21 Jul 2021, 3:40 p.m.
Panel Version: 2.41
As reported by expert reviewer 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. All five tested patients showed evidence of skewed x chromosome inactivation. In all 7 their phenotypic features include cleft lip or palate or both. Hardikar syndrome is noted for the preserved neurodevelopment in patients unlike the other disorders associated with this gene.Created: 21 Jul 2021, 3:39 p.m. | Last Modified: 21 Jul 2021, 3:39 p.m.
Panel Version: 2.40
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Hardikar syndrome, OMIM:612726; cholestasis-pigmentary retinopathy-cleft palate syndrome, MONDO:0012997
Publications
7 female individuals (2 previously reported and 5 unpublished) reported with a clinical diagnosis of Hardikar syndrome (rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation, but normal cognition). Exome sequencing identified de novo pathogenic nonsense and frameshift variants in MED12 in all 7 individuals. Evidence of extremely skewed XCI in all patients with informative testing.
Note: pathogenic missense variants in MED12 associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males.Created: 19 Apr 2021, 9:01 a.m. | Last Modified: 19 Apr 2021, 9:01 a.m.
Panel Version: 2.24
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Hardikar syndrome, OMIM #612726
Publications
Stathopulu et al. (2003, PMID 12784307) describe a 16-year-old male with phenotypic features of Lujan-Fryns syndrome and a submucous cleft palate. Little literature linking Opitz-Kaveggia syndrome and clefting. Rated red as clefting does not appear to be a major phenotype in MED12-associated disorders.Created: 31 May 2017, 11 a.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Lujan-Fryns syndrome, 309520, Opitz-Kaveggia syndrome, 305450; OKS; submucous cleft palate
Publications
Tag Q3_21_MOI was removed from gene: MED12.
Tag Q3_21_rating was removed from gene: MED12. Tag Q3_21_expert_review was removed from gene: MED12.
Source NHS GMS was added to MED12. Source Expert Review Green was added to MED12. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_21_MOI tag was added to gene: MED12.
Tag Skewed X-inactivation tag was added to gene: MED12.
Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Tag Q3_21_expert_review tag was added to gene: MED12.
Phenotypes for gene: MED12 were changed from Lujan-Fryns syndrome, 309520; Opitz-Kaveggia syndrome, 305450; OKS; submucous cleft palate to Hardikar syndrome, OMIM:612726; cholestasis-pigmentary retinopathy-cleft palate syndrome, MONDO:0012997
Publications for gene: MED12 were set to 12784307
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)
Gene: med12 has been classified as Amber List (Moderate Evidence).
Tag Q3_21_rating tag was added to gene: MED12.
Panel reviews were assessed, and panel was revised according to reviews and further curation 31st May 2017
Phenotypes for MED12 were set to Lujan-Fryns syndrome, 309520; Opitz-Kaveggia syndrome, 305450; OKS; submucous cleft palate
MED12 was added to Cleftingpanel. Sources: Expert Review Red
MED12 was created by ellenmcdonagh