ClinVar

In 7 individuals from 5 unrelated families of various ethnic descent (Italian, Middle Eastern, North African) with neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities (NDDRSB; 620327), Cali et al. (2022) identified a recurrent homozygous c.325C-T transition (c.325C-T, NM_001001683.4) in exon 3 of the MED11 gene, resulting in an arg109-to-ter (R109X) substitution in the C-terminal region and loss of the last 9 conserved residues of the protein. The patients were ascertained through international collaborative efforts, such as Matchmaker Exchange, after exome or genome sequencing identified the mutation. Three of the families were consanguineous. The mutations, which were confirmed by Sanger sequencing, segregated with the disorder in all families. R109X was present in 14 of over 500,000 exomes/genomes in public databases, but only in the heterozygous state. Haplotype analysis excluded a founder effect. Fibroblasts derived from 1 of the patients showed normal MED11 transcript and protein levels, suggesting the mutant transcript escaped nonsense-mediated mRNA decay as it was located in the last exon. Molecular modeling indicated that the C-terminal region of MED11 harboring the R109X mutation interacts with and forms a structure with MED28 (610311), MED30C (610237), and MED22 (185641); the authors concluded that the R109X mutation may affect the binding of MED11 to other MED subunits.