Early onset or syndromic epilepsy

Gene: MED12

After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed and remains 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.

Panel Version: 3.29

Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct although consideration should be given to the carrier implications for the predominantly male-only phenotypes associated with this gene.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
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. No seizures were noted.

Created: 30 Sep 2021, 3:24 p.m. | Last Modified: 4 Oct 2021, 2:02 p.m.

Panel Version: 2.434

Green List (high evidence)

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

I don't know

Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.

Created: 7 Sep 2019, 11:39 a.m. | Last Modified: 7 Sep 2019, 11:39 a.m.

Panel Version: 1.282

Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Comment on mode of inheritance: Allelic requirement listed in Gene2Phenotype is 'hemizygous' for both 'OPITZ-KAVEGGIA SYNDROME' and 'LUJAN-FRYNS SYNDROME'.

Created: 13 Aug 2019, 1:07 p.m. | Last Modified: 13 Aug 2019, 1:07 p.m.

Panel Version: 1.208

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

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
Lujan-Fryns syndrome 309520 XLR; Ohdo syndrome, X-linked 300895 XLR; Opitz-Kaveggia syndrome 305450 XLR

Publications

• 17334363

Comment on list classification: Promoted from amber to green, based on the information provided previously.

Created: 26 Nov 2018, 4:25 p.m.

Variants in MED12 are associated with 3+ intellectual disability syndrome (Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome are the ones mentioned on OMIM). The overall phenotype for each syndrome seems to overlap and the criteria used to distinguish between the different syndromes can be different for each paper.

There is one report (PMID: 17369503) of a family with two affected members diagnosed with Lujan-Fryns syndrome with a missense variant in MED12 and only one has seizures. There are three reports of different patients of different ethnicity who were diagnosed with Opitz-Kaveggia syndrome and 4 have the c.288C>T variant and have seizures, and one family with 4 affected members with Opitz-Kaveggia syndrome and a duplication variant in MED12.

Created: 23 Nov 2018, 1:25 p.m.

Green List (high evidence)

Seizures are part of the phenotype of this intellectual disability syndrome.

Created: 16 Aug 2018, 11:58 a.m.

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

Phenotypes
Lujan-Fryns syndrome, MIM#309520

Variants in this GENE are reported as part of current diagnostic practice