De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Blok, Lot Snijders; Hiatt, Susan M.; Bowling, Kevin M.; Prokop, Jeremy W.; Engel, Krysta; Cochran, J. Nicholas; Bebin, E. Martina; Bijlsma, Emilia K.; Ruivenkamp, Claudia; Terhal, Paulien A; Simon, Marleen; Smith, Rosemarie; Hurst, Jane A.; McLaughlin, Heather; Person, Richard; Crunk, Amy; Wangler, Michael F.; Streff, Haley; Symonds, Joseph D.; Zuberi, Sameer M.; Elliott, Katherine S.; Sanders, Victoria R.; Masunga, Abigail; Hopkin, Robert J.; Dubbs, Holly; Ortiz-González, Xilma R.; Pfundt, Rolph; Brunner, Han G.; Fisher, Simon E.; Kleefstra, Tjitske; Cooper, Gregory M.

doi:10.1007/s00439-018-1887-y

Cited by 56 publications

(58 citation statements)

References 48 publications

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“…For many of the genes listed in Table S1 (see families M9300163, M9300035, M9300014, M8800189 and M8900019), mutations in patients with ID have only been reported very recently, including VPS13C ; BOD1, TTI1, NEURL4 ; ATP13A1, a paralog of ATP13A2 , which is associated with autosomal recessive early‐onset parkinsonism, ceroid lipofuscinosis and ID, as well as MED13 . Thus, our study confirms their identity as ID genes.…”

Section: Resultsmentioning

confidence: 99%

Effect of inbreeding on intellectual disability revisited by trio sequencing

Kahrizi

Hosseini

et al. 2018

Clinical Genetics

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In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near‐ and middle‐east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole‐exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6‐fold, and about 4.1 to 4.25‐fold for children of first‐cousin unions. These results do not rhyme with recent opinions that consanguinity‐related health risks are generally small and have been “overstated” in the past.

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Section: Resultsmentioning

confidence: 99%

Effect of inbreeding on intellectual disability revisited by trio sequencing

Kahrizi

Hosseini

et al. 2018

Clinical Genetics

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“…Therefore, another interpretation of the knockout results is that removing Med13 or Med13L may invoke a gene dosage-related phenotype. For example, recent studies found that MED13 or MED13L haploinsufficiency results in several overlapping, but not identical, developmental syndromes (41)(42)(43)(44)(45)(46). Therefore, transcriptional control by Med13 and Med13L may be exquisitely sensitive to gene copy number.…”

Section: Discussionmentioning

confidence: 99%

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

Stieg

Cooper

Strich

2020

Journal of Biological Chemistry

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The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C and one each of paralogs Cdk8/Cdk19, Med12/Med12L and Med13/Med13L. Our previous RNA-seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide-induced genes under normal conditions, but is involved in activating other loci following stress. Here, we show that cyclin C directs this transcriptional re-programing through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C indicating that the CKM moves as a single unit. It has previously been shown that some cyclin C leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. We observed that CKM integrity appeared compromised at a subset of repressed promoters suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters suggesting a mechanism to generate gene- and stress-specific responses.

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“…• Similarly, subjects with haplo-insufficiently of MED13L show ID and severe speech delay; congenital heart defects are found in 20-50% of patients 79,81 . In preclinical studies, haploinsufficiency of MED13L shows defects in both neuronal migration and differentiation 82,83 . • ADNP variants are reported in children with autism and ID who carry a diagnosis of Helsmoortel-Van der Aa syndrome 84 .…”

Section: Genementioning

confidence: 99%

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Ji¹,

Ferdman²,

Copel³

et al. 2020

Sci Rep

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congenital heart disease (cHD) survivors are at risk for neurodevelopmental disability (nDD), and recent studies identify genes associated with both disorders, suggesting that nDD in cHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that nDD in cHD may be attributable to genes altering both neural connectivity and cardiac patterning. to assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. cHD cases had more protein truncating and deleterious missense DnVs among connectome genes compared to controls (oR = 5.08, 95%CI:2.81-9.20, Fisher's exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02-6.73, Fisher's exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11,

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De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Cited by 56 publications

References 48 publications

Effect of inbreeding on intellectual disability revisited by trio sequencing

Effect of inbreeding on intellectual disability revisited by trio sequencing

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

De novo damaging variants associated with congenital heart diseases contribute to the connectome

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