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

Abstract

Background: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. Methods: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. results: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. conclusion: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/ MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.

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

“…Based on these particular palpebral features, P20 was initially diagnosed with Kabuki syndrome (OMIM #147920). All these data are supported by clinical features from the 11 patients reported in the literature, carrying missense variants [8,13,14,17]. Clinical details of the patients reported by the DDD study were retrieved from Decipher database (https://decipher.sanger.ac.uk/) and corresponded to patients' ID: #272205, #260542, #262717, #258131, #268019, #262545, #265953, and #323183.…”

“…Strikingly, no further dTGA was found and all patients presented with ID, characteristic facial gestalt, and less commonly aspecific CHD in 6/25 cases (patent foramen ovale, Fallot tetralogy, pulmonary atresia). To our knowledge, seven missense variants were identified in 11 patients, but the lack of precise clinical data in most of them precluded clarification of their clinical relevance or possible genotypephenotype correlation [8,13,14,17]. Here, we report on 36 patients with MED13L variations affecting its function, including seven missense variants in nine patients.…”

“…Recently, MED13L haploinsufficiency have been identified in patients with moderate to severe ID, hypotonia, and distinctive facial gestalt (OMIM #616789) [6][7][8][9][10]. The recognizable syndrome was delineated by Asadollahi et al [7] and broadened by further reports [6,8,[10][11][12][13][14][15]. The gene is located on chromosome 12q24.…”

MED13L loss‐of‐function variants in two patients with syndromic Pierre Robin sequence

“…The patient in that report shared many other features with the two patients we present here but unfortunately no photographs or growth parameters were provided. Interestingly, micrognathia and/or retrognathia has been reported in seven further patients, (Asadollahi et al, , ; Caro‐Llopis et al, ; van Haelst et al, ) and cleft palate in one patient (Cafiero et al, ). The two patients we report share postnatal overgrowth with head circumference remaining in the normal range.…”

“…Since this initial report, learning difficulties and/or ID have been consistently reported as a feature of this group of disorders. A homozygous missense mutation has been reported in two patients with non‐syndromic ID (Najmabadi et al, ) while a balanced translocation, missense and truncating mutations and intragenic and large deletions and duplications encompassing MED13L have been reported in patients with syndromic ID (Adegbola et al, ; Asadollahi et al, , ; Cafiero et al, ; Caro‐Llopis et al, ).…”