Intellectual disability - microarray and sequencing
Gene: MED25Comment on list classification: Updated rating from Amber to Green based on the recent Lebanese cases reported by Nair et al (DOI:10.1159/000501114 and PMID:30800049). Advice and a Green review by Helen Brittain supports the upgrade to Green.Created: 10 Oct 2019, 11:52 a.m. | Last Modified: 10 Oct 2019, 11:52 a.m.
Panel Version: 2.1066
DOI:10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.Created: 26 Sep 2019, 8:12 p.m. | Last Modified: 26 Sep 2019, 8:13 p.m.
Panel Version: 2.1046
PMID:30800049 (Nair et al., 2019) report on a girl, born to first-cousin Lebanese parents, with severe ID and seizures amongst her various phenotypes. Homozygous variants were found in both MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp), and were both present in heterozygous states in the parents. Both variants are VUS according to ACMG guidelines, have low frequency in GnoMAD in heterozygous state, and pathogenic predictions vary between programmes. The authors propose that the variants may act together to cause the phenotype but functional studies or further investigations were not performed.Created: 26 Sep 2019, 8:12 p.m. | Last Modified: 26 Sep 2019, 8:12 p.m.
Panel Version: 2.1046
Please consider the 2 additional articles by Nair et al. (2019 - DOI: 10.1159/000494465 - PMID: 30800049 & DOI: 10.1159/000501114 - PMID: NA) reporting on 3 individuals from 2 consanguineous Lebanese families. All affected individuals were homozygous for a MED25 missense variant [NM_030973.3:c.518T>C / p.Ile173Thr], possibly a founder mutation in the Lebanese population. The phenotype presented some similarities with the previously described patients. The variant has a very low AF in gnomAD (0.00003470) and was also absent from the Saudi Variant Database. In silico predictions from PolyPhen2, PROVEAN, MutationTaster were suggestive of a probably damaging effect. The individual from the first report (PMID: 30800049) had an additional homozygous COQ8A variant, with some features fitting with the phenotype of AR primary CoQ10 deficiency type 4 and others negating this (possibly concurrent) diagnosis.
MED25 is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc, Victorian Clinical Genetics and many others). It is not however included in the DD panel of G2P.Created: 1 Sep 2019, 5:09 p.m. | Last Modified: 1 Sep 2019, 5:14 p.m.
Panel Version: 2.1021
Phenotypes
Basel-Vanagait-Smirin-Yosef syndrome (MIM 616449)
Publications
Variants in this GENE are reported as part of current diagnostic practice
There are now different variants (potentially each founders) in three populations, and several families, that have been reported in association with ID. Therefore the evidence for a green rating in terms of a gene:disease association now seems sufficient. To determine the extent of the phenotype, in terms of associated features, further cases would be beneficial. Therefore I would currently recommend a green rating for the ID panel.Created: 4 Oct 2019, 1:29 p.m. | Last Modified: 4 Oct 2019, 1:29 p.m.
Panel Version: 2.1062
Comment when marking as ready: It is interesting as both populations studied are highly consanguineous and aside from ID, the phenotype is not clearly the same. The facial features are not clearly in keeping (although the images shown are from very different points in life and coarsening over time could be envisaged). Also, one cohort had ocular features whereas the other doesn't. Further cases are needed, preferably from alternative backgrounds to inform about causation and the associated core phenotype. Amber and watchlist is appropriate.Created: 8 Mar 2018, 3:04 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Basel-Vanagait-Smirin-Yosef syndrome 616449
As a result of watchlist tag audit the watchlist tag was removed from MED25- this is now a green gene with sufficient evidence/reviewCreated: 13 Jan 2020, 3:41 p.m. | Last Modified: 13 Jan 2020, 3:41 p.m.
Panel Version: 3.0
watchlist and founder-effect tags addedCreated: 8 Mar 2018, 3:52 p.m.
Comment on list classification: changed from Red to Amber- for clinical review. Possible founder effect but also consideration of two papers describe families from two distinct regions Palestine and Northeastern Brazil. All cases with a form of ID.Created: 7 Mar 2018, 5:14 p.m.
Comment on publications: In the same year Figueiredo T et al,. (2015) PMID: 25527630 found a homozygous missense p.(Arg140Trp) mutation in MED25 in a large consanguineous family from Northeastern Brazil in which seven adults were diagnosed with syndromic intellectual disability.Created: 7 Mar 2018, 4:58 p.m.
Comment on publications: Basel-Vanagaite et al. (2015) PMID: 25792360 reported 7 children from 4 unrelated families living in the same small village in Israel with a severe syndromic neurodevelopmental disorder. All had severely delayed psychomotor development apparent from infancy and variable eye abnormalities, including ptosis, microcornea, and congenital cataracts. None of the children was able to speak or walk independently, including the oldest, who was 13 years old. The study showed that a homozygous mutation p.(Tyr39Cys)in MED25 was responsible for a previously undescribed syndrome characterized by severe intellectual disability, characteristic dysmorphic features, congenital eye abnormalities, corpus callosum abnormalities and other congenital abnormalities. They identified a carrier rate of 8.7 % among the inhabitants of the village from which all the families described in this study originated. The high prevalence of the mutation can be explained both by the founder effect owing to the generally high consanguinity rate among the inhabitants of the village, and also because several families in this village had excessive numbers of intellectually disabled offspring due to founder mutations of other genes related to intellectual disability.Created: 7 Mar 2018, 4:55 p.m.
Comment on phenotypes: added relevant phenotype from OMIM, Orphanet and PMID:25527630Created: 7 Mar 2018, 3:08 p.m.
Added the 'watchlist' tag to carry out thorough literature search to assess the evidence for this variant.Created: 21 Feb 2017, 10:35 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
syndromic intellectual disability; Basel-Vanagait-Smirin-Yosef syndrome 616449; ?Charcot-Marie-Tooth disease, type 2B2 605589
Publications
Tag watchlist was removed from gene: MED25.
Gene: med25 has been classified as Green List (High Evidence).
Publications for gene: MED25 were set to 25792360; 25527630
Source Victorian Clinical Genetics Services was added to MED25.
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.
Expert Review Amber was added to MED25. Panel: Intellectual disability
MED25 was added to Intellectual disabilitypanel. Sources: Literature
MED25 was created by ellenmcdonagh