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| Intellectual disability - microarray and sequencing v4.53 | MED13 |
Arina Puzriakova Tag Q2_22_rating was removed from gene: MED13. Tag Q2_22_NHS_review was removed from gene: MED13. |
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| Intellectual disability - microarray and sequencing v4.53 | MED13 | Arina Puzriakova reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.52 | MED13 |
Arina Puzriakova Source NHS GMS was added to MED13. Source Expert Review Green was added to MED13. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v3.1653 | MED13L | Arina Puzriakova Publications for gene: MED13L were set to 23403903 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1652 | MED13L | Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1590 | MED13 |
Catherine Snow Tag Q2_22_rating tag was added to gene: MED13. Tag Q2_22_NHS_review tag was added to gene: MED13. |
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| Intellectual disability - microarray and sequencing v3.1590 | MED13 | Catherine Snow reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33931951; Phenotypes: Intellectual developmental disorder, autosomal dominant 61 OMIM:618009; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1044 | MED13 | Rebecca Foulger Classified gene: MED13 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1044 | MED13 | Rebecca Foulger Gene: med13 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1043 | MED13 | Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published.; to: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Not yet associated with a disorder in OMIM. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1043 | MED13 | Rebecca Foulger Classified gene: MED13 as No list | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1043 | MED13 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1043 | MED13 | Rebecca Foulger Gene: med13 has been removed from the panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1021 | MED13 |
Konstantinos Varvagiannis changed review comment from: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations. Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted. MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders. 3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case). Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?). Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13. The remaining missense variants affected the C-terminal portion (Q2060L, A2064V). As a result the impact of the different subcategories of variants remains unclear/inconclusive. MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes). MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene. Sources: Radboud University Medical Center, Nijmegen, Literature; to: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations. Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted. MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders. 3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case). Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?). Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13. The remaining missense variants affected the C-terminal portion (Q2060L, A2064V). As a result the impact of the different subcategories of variants remains unclear/inconclusive. MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes). MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ID is part of the phenotype of MED13-related disorder. However as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating seems more appropriate. Sources: Radboud University Medical Center, Nijmegen, Literature |
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| Intellectual disability - microarray and sequencing v2.1021 | MED13 |
Konstantinos Varvagiannis gene: MED13 was added gene: MED13 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature Mode of inheritance for gene: MED13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MED13 were set to 29740699 Phenotypes for gene: MED13 were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Attention deficit hyperactivity disorder; Abnormality of the eye; Constipation Penetrance for gene: MED13 were set to unknown Review for gene: MED13 was set to AMBER gene: MED13 was marked as current diagnostic Added comment: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations. Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted. MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders. 3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case). Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?). Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13. The remaining missense variants affected the C-terminal portion (Q2060L, A2064V). As a result the impact of the different subcategories of variants remains unclear/inconclusive. MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes). MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene. Sources: Radboud University Medical Center, Nijmegen, Literature |
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| 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 | MED13L | Louise Daugherty Source Victorian Clinical Genetics Services was added to MED13L. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||