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| Intellectual disability - microarray and sequencing v3.1519 | MED12 |
Ivone Leong Tag Q3_21_MOI was removed from gene: MED12. Tag Q3_21_expert_review was removed from gene: MED12. |
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| Intellectual disability - microarray and sequencing v3.1519 | MED12 | Sarah Leigh commented on gene: MED12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1519 | MED12 |
Ivone Leong 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) |
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| Intellectual disability - microarray and sequencing v3.1315 | MED12 |
Eleanor Williams 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. |
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| Intellectual disability - microarray and sequencing v3.1315 | MED12 | Eleanor Williams changed review comment from: 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.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1315 | MED12 | Eleanor Williams Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1315 | MED12 | Eleanor Williams 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1314 | MED12 | Eleanor Williams Publications for gene: MED12 were set to 6711603 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1313 | MED12 | Eleanor Williams edited their review of gene: MED12: Changed publications to: 33244165, 34079076, 33244166 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1313 | MED12 | Eleanor Williams reviewed gene: MED12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.876 | MED12L | Eleanor Williams Classified gene: MED12L as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.876 | MED12L | Eleanor Williams Gene: med12l has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.875 | MED12L | Eleanor Williams commented on gene: MED12L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.857 | MED12L |
Konstantinos Varvagiannis gene: MED12L was added gene: MED12L was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MED12L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MED12L were set to 31155615 Phenotypes for gene: MED12L were set to Motor delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Abnormality of the abdomen; Seizures; Abnormality of the corpus callosum Penetrance for gene: MED12L were set to unknown Review for gene: MED12L was set to AMBER Added comment: Nizon et al. (2019 - PMID: 31155615) report on 7 unrelated individuals with nucleotide or copy-number variants in MED12L. Features included motor delay (4/7), speech impairment (7/7) with ID of variable degrees (7/7 - mild to severe). Variable behavioral abnormalities (ASD in 4/7, aggressive behavior, ADHD, etc), functional GI anomalies, corpus callosum abnormalities and seizures were among other features noted in some/few. There was no recognizable facial phenotype. Nucleotide variants included 1 stopgain, 1 frameshift and 2 splice site variants. 3 CNVs were reported (two 3q25.1 microduplications of 460- and 147-kb respectively and one microdeletion of 291-kb) although all spanned also other genes. De novo occurrence was shown for 2 CNVs and 2 SNVs, as parental samples were unavailable for 3 of the subjects. Contribution of other genetic (eg. an inherited 22q11.2 microduplication, VUS in other genes) or environmental factors could not be ruled out for few individuals. Among the arguments provided: MED12L encodes a subunit of the kinase module of the mediator complex, a complex required for transcription by RNA polymerase II. Mutations in other subunits of the kinase module (eg. MED12, MED13L, etc) have been implicated in intellectual disability. The protein is localized in the nucleus. The gene is mainly expressed in the brain. The functional effect of 2 CNVs was evaluated using the recovery of RNA synthesis assay, an assay reflecting global transcriptional activity. Fibrobast studies from one individual with microdeletion and one further subject with microduplication demonstrated decreased RNA synthesis compared to controls. Decreased RNA synthesis was also observed in cell lines from individuals with mutations in other genes for subunits of the mediator complex (eg. MED12 or MED13L) or from individuals with Cockayne syndrome. Therefore haploinsufficiency is suggested to underly the transcriptional defect. (MED12L also appears to be intolerant to LoF variation with a pLI score of 1). Some features appear to be common among the disorders caused by pathogenic variants in MED12L or other subunits of the kinase module (MED12, MED13, MED13L) eg. ID, abnormal behaviour or autistic features. Animal models are not discussed / (probably not) available (MGI for Med12l : http://www.informatics.jax.org/marker/MGI:2139916). MED12L is not associated with any phenotype in OMIM or G2P. The gene is not commonly included in gene panels for ID offered by diagnostic laboratories. As a result, this gene can be considered for inclusion in the ID panel, probably as amber (4 variants affecting only MED12L, segregation studies performed for 2, degree of ID reported mild on 2 occasions) pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.787 | CDK8 |
Konstantinos Varvagiannis commented on gene: CDK8: Calpena et al. (2019 - PMID: 30905399 - DDD study among the co-authors) report on 12 unrelated individuals with pathogenic CDK8 missense variants. Common features included hypotonia and DD (universal feature). Older children displayed variable degrees of ID (2 mild, 5 moderate, 2 moderate-severe). Other features included feeding difficulties, behavioral disorders, CHD, epilepsy (2 individuals), impaired vision and hearing problems in few. CDK8 (alternatively CDK19) serves a one of the four subunits of a kinase module that reversibly binds to the mediator complex to regulate its activity (in turn, regulation of transcription). Mutations in other genes coding for the 3 other subunits of the kinase module (eg. MED12 or MED13L) lead to syndromic neurodevelopmental disorders. 8 missense CDK8 variants were reported in total. Ser62Leu (NM_001260.2:c.185C>T) was recurrent, observed in 5 subjects. The variants had occurred as de novo events in all cases (10 individuals) where parental samples were available. All variants clustered in the kinase domain (residues 21-335 - of 464 total) around the ATP binding pocket. A thermal stability assay did not reveal gross protein instability in the presence or absence of ATP while the ability to bind ATP was retained for most/all variants. Study of STAT1 phosphorylation was suggestive of attenuated kinase activity for all variants, though to a lesser degree for 2 of them. Given the type of variants (all missense) and the pLI of 0.38 haploinsufficiency appears to be unlikely. A dominant-negative mechanism is favoured. CDK8 is not associated with any phenotype in G2P. As a result, CDK8 can be considered for upgrade to green or amber (if the degree of ID is relevant for the current panel). |
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| Intellectual disability - microarray and sequencing v2.468 | MED12 | Louise Daugherty Source Victorian Clinical Genetics Services was added to MED12. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | MED12 | BRIDGE consortium edited their review of MED12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | MED12 | BRIDGE consortium edited their review of MED12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | MED12 | BRIDGE consortium reviewed MED12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||