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.

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

“…Our results support the findings reported by Adegbola et al (17) regarding the absence of congenital heart disease Gly2040Asnfs*32 (14) Gln1984Alafs*31 (17) (17) (17) Based exclusively on the clinical features, patients with mutations in the MED12 gene were previously classified in three different clinical syndromes, although all of them share in common, to a greater or lesser degree, the same clinical findings: somatic growth disorders (affecting weight and/or height), altered size of the head, micrognathia, philtrum anomalies, some dysmorphic facial features, genitourinary anomalies, abnormal hands and feet, in addition to problems in the central nervous system (agenesis of corpus callosum, seizures, autistic and/or hyperactive behavior, intellectual disability and developmental delay) (reviewed in refs. (11,18,19)).…”

“…(11,18,19)). A very similar scenery has been found among the patients with mutations in the MED13L gene, who present a wide phenotypic spectrum which basically includes the same clinical features found in association to mutations in the MED12 (13,17,20,21).…”

“…All individuals had intellectual disability and share characteristic facial features, delayed speech and language development, hypotonia, poor coordination, and behavioral problems. None of the patients had a complex congenital heart defect (17).…”

Coupling clinical exome sequencing with functional characterization studies to diagnose a patient with familial Mediterranean fever and MED13L haploinsufficiency syndromes

“…However, based on the most recent summary of DEAF1 patients, these patients have a more severe motor delay, severe delay in expressive speech (absent speech to ten single words), and very severe intellectual disability compared with our patient . Closer examination of the MED13L haploinsufficiency syndrome phenotype, through analyzing the 21 known reported MED13L variant cases , showed that our patient is similar to other MED13L haploinsufficiency cases (Table ). Further, similar missense mutations of MED13L that occur later in the protein in the C‐terminal region have a milder phenotype in terms of ID and language development .…”

“…Comparing the phenotype of our patient to the core phenotypes of MED13L haploinsufficiency syndrome and DEAF1 ‐associated syndrome, it was apparent that both of these syndromes could fit with our patient's phenotype (Fig. ).…”