MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype

Abstract

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Is MED13L-related intellectual disability a recognizable syndrome?

“…Microphthalmia has also been reported in another patient with a missense variant, and in a patient with a splice site variant (7). We agree with Smol et al (7) and hypothesize that missense variants might induce a dominant negative effect, in contrast to truncating variants.…”

“…This supports that patients with missense variants seem to frequently have a more severe phenotype with hypotonia, absent speech, and severely delayed motor function, compared to patients with truncating variants (5,7). Microphthalmia has also been reported in another patient with a missense variant, and in a patient with a splice site variant (7). We agree with Smol et al (7) and hypothesize that missense variants might induce a dominant negative effect, in contrast to truncating variants.…”

“…Missense variants in MED13L are reported to cluster in exons 15-17 and 25-31 (7), which also holds true for our missense variant which is located in exon 17.…”

“…Recently, Smol et al (7) described 36 additional cases and the involvement of missense variants, that seems to cause a more severe phenotype, frequently with epilepsy, and absent ability to speak and walk.…”

“…More than 70 patients with definite or suspected MED13L-related intellectual disability have been reported so far. In 61 patients, the phenotype was described in detail (1)(2)(3)(4)(5)(6)(7)(8)(14)(15)(16). Features of these 61 patients and our 8 patients are listed in Table 2, which serve as basis of the review.…”