Redefining the MED13L syndrome

Abstract

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.

Figure 1

Phenotype and genotype of patients with MED13L gene mutations. (a) Pictures of index patients 1–9 illustrating the typical facial features including a broad forehead, bitemporal narrowing, low set ears, upslanted palpebral fissures, flat nasal root, broad nasal tip, macrostomia with an open-mouth appearance and frontal bossing. (b) Skeletal features include fifth finger clinodactyly (index patient 2), arthrogryposis and ulnar deviated club hands, as well as camptodactyly of the toes and cutaneous syndactyly of toes 2–3 (index patient 5), clinodactyly of the fifth rays of both hands (index patient 6) and short thumbs (index patient 7). (c) Diagrammatic presentation of the MED13L gene with exons 1–31 (intronic regions are not drawn to scale). The mutations identified in the index patients reported here are highlighted in bold print, and previously published mutations are indicated in normal print.