Non-syndromic familial congenital anorectal malformations

Gene: MED12

Green List (high evidence)

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

Phenotypes
FG syndrome

Comment on mode of inheritance: Updating the mode of inheritance to X-linked: hemizygous mutation in males, monallelic mutations in females after advice from the Genomics England clinical team. There are 5 reported relevant cases in females.

Created: 10 Nov 2021, 11:53 a.m. | Last Modified: 10 Nov 2021, 11:53 a.m.

Panel Version: 1.8

Comment on mode of inheritance: Leaving the mode of inheritance as biallelic in females just now but noting that a few female cases have been reported, mainly with skewed x-chromosome inactivation.

Created: 4 Oct 2021, 1:41 p.m. | Last Modified: 4 Oct 2021, 1:41 p.m.

Panel Version: 1.7

De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - 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. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and one of the three additionally presented with anal stenosis . 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. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.

Created: 3 Oct 2021, 3:04 p.m. | Last Modified: 4 Oct 2021, 1:39 p.m.

Panel Version: 1.6

Note that in Gene2Phenotype the Mutation consequence summary is "uncertain".

Created: 1 Nov 2018, 1:12 p.m.

Comment on list classification: Rated green as more than 3 families with the R961W variant show a relevant phenotype.

Created: 8 Oct 2018, 8:39 p.m.

MED12 is associated with Opitz-Kaveggia syndrome (also known as FG syndrome and FG syndrome 1) in OMIM and Gene2Phenotype (confirmed). Opitz-Kaveggia syndrome (OKS) is an X-linked recessive mental retardation syndrome characterized by dysmorphic features, but phenotypes relevant to this panel also include anal stenosis, imperforate anus, anteriorly placed anus and constipation.

As stated in OMIM Risheg et al 2007 (PMID: 17334363) reported that the original family from which the designation FG was derived and 5 other families had a recurrent mutation in the MED12 gene, R961W. Imperforate anus, wide flat thumbs, and wide great toes were present in 7 of 10 cases. Failure to find the change in 451 normal men and in 343 consecutive newborn males suggested that it is not a rare polymorphic variant. The finding of the mutation in patients of various ethnic backgrounds suggested that families did not share a common ancestor.

Ding et al. (2008) (PMID: 18691967) showed that the R961W substitution disrupts the REST corepressor function of MED12.

Other variants in MED12 are linked to other syndromes such as LUJAN-FRYNS SYNDROME and OHDO SYNDROME, X-LINKED.

Created: 8 Oct 2018, 8:38 p.m.

Comment on list classification: Rated gene amber as is on expert list

Created: 19 Sep 2018, 4:19 p.m.

Gene added from expert list from Dr Charles Shaw-Smith (Royal Devon and Exeter NHS Foundation Trust) who has associated it with FG syndrome (also known as Opitz-Kaveggia syndrome)

Created: 19 Sep 2018, 4:19 p.m.