Submission Details

Intragenic deletions in MED13L were first reported in patients with syndromic intellectual disability in 2013 (Asadollahi et al., PMID: 23403903). Individuals with loss-of-function (LoF) variants in MED13L present with moderate to severe intellectual disability, muscular hypotonia and facial anomalies (PMIDs: 28645799, 29511999). Additional features observed in 20%-50% of patients include severe speech delay, abnormal brain MRI, ataxia, and autistic features; cardiac anomalies have been reported in about 17% of patients (PMIDs: 28645799, 29511999). De novo LoF variants, including large intragenic deletions, nonsense, frameshift and splice site variants have been reported in over 30 probands in 5 publications (PMIDs: 23403903, 24781760, 25712080, 27500536, 29511999). Other individuals with MED13L variants have been reported in the literature, but they were not included in this curation since the maximum score for genetic evidence had been reached. At least 13 individuals with de novo missense variants presented with similar but more severe phenotypes and with a higher frequency of seizures than observed in patients with LoF variants (PMIDs: 32646507, 24896178, 27500536, 28645799, 29593475, 29511999). Probands with a missense variant were not counted towards genetic evidence since functional data supporting pathogenicity of missense variants was not available. The mechanism of disease is haploinsufficiency of MED13L (PMIDs: 23403903, 25137640). The gene-disease relationship is supported by a model organism, rescue experiments, protein interaction, and biochemical function data. In summary, MED13L is definitively associated with autosomal dominant syndromic intellectual disability (PMID: 29209056). The classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 04/21/21 (SOP Version 8).