Two de novo loss-of-function variants in the MED13L gene have been identified in ASD probands from the Simons Simplex Collection (refs).
The protein encoded by this gene is a subunit of the Mediator complex, a large complex of proteins that functions as a transcriptional coactivator for most RNA polymerase II-transcribed genes. The encoded protein is involved in early development of the heart and brain. Defects in this gene are a cause of transposition of the great arteries, dextro-looped (DTGA) [MIM:608808].
Type of Disorder
De novo gene disruptions in children on the autistic spectrum.
Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).
Category 2 - Strong Candidate
Rare mutations that are recurrent and convincing accompanied by a rigorous statistical comparison with the mutation frequency in controls. Independent replication is not required. Full sequencing of a comparable number of cases and controls is required. Convincing is defined as ?likely to be functional?, or showing perfect segregation of mutations and phenotype in a large pedigree. Rare de novo variants, likely to be disruptive, in three or more unrelated cases would qualify here.