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Photograph of the patient. The picture shows microcephaly, frontal bossing, low-set ears, hypertelorism, epicanthus, depressed nasal bridge, bulbous nasal tip, cupid-bow upper lip combined with open mouth appearance, micrognathia, muscular atrophy
Source publication
Background:
MED13L-related intellectual disability is a new syndrome that is characterized by intellectual disability (ID), motor developmental delay, speech impairment, hypotonia and facial dysmorphism. Both the MED13L haploinsufficiency mutation and missense mutation were reported to be causative. It has also been reported that patients carrying...
Context in source publication
Context 1
... extremities as well as hyperlaxity of the joints. She had scoliosis and had spontaneous fracture of the distal right femur at 1 year old. Abnormal facial deformity includes frontal bossing, low-set ears, hypertelorism, epicanthus, depressed nasal bridge, bulbous nasal tip, cupid-bow upper lip combined with open mouth appearance and micrognathia (Fig. 1). From 3 years and 4 months old, she had unconscious frequent odontoprisis. Her developmental milestones were severely delayed, as she raised her head at 1 year. At the last evaluation, the girl was 4 years and 5 months old, and she could not yet sit or stand without support, let alone walk. Her speech was also severely delayed; she can ...
Citations
... MED13 is ubiquitous in human tissues, with the highest expression found in the placenta, skeletal muscle, heart, pancreas, and brain [23]. The major role of the complex was indeed proven by the discoveries of multiple patient cases with de novo variants in the genes encoding Mediator subunits, such as MED12 [24], CDK8 [25], MED13L [26], and others. The patients carrying MED13 variants are also suffering neurodevelopmental disorders that are in many cases accompanied by heart anomalies, motor delay, dysmorphic features, microcephaly, deafness, retinal dystrophy and corpus callosum abnormalities [16][17][18][19][20]. ...
... For MED13 and MED13L, parts of the Mediator complex, both missense and lossof-function variants were reported as pathogenic. Notably, missense changes in MED13L were described in association with a more severe phenotype-patients having higher incidence of seizures, MRI abnormalities, autistic features, and cardiac anomalies [26]; thus, we speculated that it might be the same for MED13 protein, and compared clinical features in respect to the variant type (missense vs. loss-of-function). So far, 13 patients carrying MED13 missense and in-frame amino acid deletion variants were described in the literature [16][17][18][19][20] and Decipher database. ...
Background
Whole exome sequencing allows rapid identification of causative single nucleotide variants and short insertions/deletions in children with congenital anomalies and/or intellectual disability, which aids in accurate diagnosis, prognosis, appropriate therapeutic interventions, and family counselling. Recently, de novo variants in the MED13 gene were described in patients with an intellectual developmental disorder that included global developmental delay, mild congenital heart anomalies, and hearing and vision problems in some patients.
Results
Here we describe an infant who carried a de novo p.Pro835Ser missense variant in the MED13 gene, according to whole exome trio sequencing. He presented with congenital heart anomalies, dysmorphic features, hydrocephalic changes, hypoplastic corpus callosum, bilateral optic nerve atrophy, optic chiasm atrophy, brain stem atrophy, and overall a more severe condition compared to previously described patients.
Conclusions
Therefore, we propose to expand the MED13-associated phenotype to include severe complications that could end up with multiple organ failure and neonatal death.
... Almost 100 individuals with suspected or confirmed MED13L haploinsufficiency syndrome have been reported to date [20][21][22][23][24][25][26][27]. According to the DECIPHER database, there are additional pathogenic MED13L deletions and duplications. ...
... Recent studies indicated that MedPIWI, which is the core globular domain of the MED13 or MED13L protein, is predicted to trigger the conformational switch in the CDK8 subunit that regulates the mediator complex. Zhang et al. (2020), by silencing MED13L in non-small-cell lung cancer cells, showed disrupted interaction between the CDK8 kinase module and the core mediator. Meanwhile, the head module, together with the middle module, plays an essential role during the assembly of the pre-initiation complex by contacting the RNA polymerase type II, thus stabilising its interaction with the DNA-binding transcription factors. ...
Background and Objectives: Heterozygous pathogenic variants in the MED13L gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789). This complex neurodevelopmental disorder is characterised by various phenotypic features, including plagiocephaly, strabismus, clubfoot, poor speech, and developmental delay. The aim of this study was to evaluate the clinical significance and consequences of a novel heterozygous intragenic MED13L deletion in a proband with clinical features of a MED13L-related disorder through extensive clinical, molecular, and functional characterisation. Materials and Methods: Combined comparative genomic hybridisation and single-nucleotide polymorphism array (SNP-CGH) was used to identify the changes in the proband’s gDNA sequence (DECIPHER #430183). Intragenic MED13L deletion was specified via quantitative polymerase chain reaction (qPCR) and Sanger sequencing of the proband’s cDNA sample. Western blot and bioinformatics analyses were used to investigate the consequences of this copy number variant (CNV) at the protein level. CRISPR-Cas9 technology was used for a MED13L-gene-silencing experiment in a culture of the control individual’s skin fibroblasts. After the MED13L-gene-editing experiment, subsequent functional fibroblast culture analyses were performed. Results: The analysis of the proband’s cDNA sample allowed for specifying the regions of the breakpoints and identifying the heterozygous deletion that spanned exons 3 to 10 of MED13L, which has not been reported previously. In silico, the deletion was predicted to result in a truncated protein NP_056150.1:p.(Val104Glyfs*5), partly altering the Med13_N domain and losing the MedPIWI and Med13_C domains. After MED13L gene editing was performed, reduced cell viability; an accelerated aging process; and inhibition of the RB1, E2F1, and CCNC gene expression were found to exist. Conclusions: Based on these findings, heterozygous intragenic 12q24.21 deletion in the affected individual resulted in MED13L haploinsufficiency due to the premature termination of protein translation, therefore leading to MED13L haploinsufficiency syndrome.
... La sévérité du phénotype s'exprime également par un retard moteur très marqué chez les patients porteurs de variations faux-sens, notamment de variations de l'exon 15. Cette observation, que nous avions pu établir à partir de l'étude de cohorte, a été confirmée par d'autres équipes (105,107,120,122). Ainsi les troubles moteurs avec une démarche ataxique associée à un retard moteur important, voire une perte de la marche, ont été observés chez plusieurs patients porteurs de variations faux-sens (62,105). ...
Les variations hétérozygotes pathogènes de MED13L provoquent un trouble du neurodéveloppement rare caractérisé par une déficience intellectuelle modérée à sévère. Le séquençage non ciblé chez des patients atteints de déficiences intellectuelles non-syndromiques a conduit à l'identification d'un nombre croissant de variations faux-sens candidates dans MED13L.Par une collaboration internationale entre des centres d'expertise pour les anomalies du développement, nous avons rapporté 36 patients présentant une variation pathogène de MED13L afin de préciser le phénotype. Cinq variantes faux-sens pathogènes provoquant soit un phénotype sévère (p.Pro866Leu, p.Pro869Ser, et p.Cys1131Tyr) soit un phénotype typique (p.Gly1899Arg et p.Thr2162Met) ont été sélectionnées et étudiées fonctionnellement. Parallèlement à l'analyse fonctionnelle, une comparaison des paramètres in silico associés aux faux-sens pathogènes précédemment publiés ou rapportées dans les bases de données témoins a été réalisée.Les variants faux-sens sont regroupés majoritairement dans les exons 15-17 et 25-31. Nous avons constaté que les patients porteurs de variations faux-sens présentaient un phénotype plus sévère avec une épilepsie fréquente. Des différences significatives ont été identifiées entre les faux-sens pathogènes et neutres pour les scores de conservation, les différences physico-chimiques entre acides aminés suivant le score de Grantham, la conservation de la séquence dans la protéine MED13 et la proximité de sites de phosphorylation. Fonctionnement, les variations p.Pro866Leu et p.Pro869Ser étaient susceptibles d'induire une hyper-phosphorylation du domaine MED13L823-930. Les résidus Cys1131 et Thr2162 pourraient impacter la conformation de MED13L avec une modification de la structure 3D. Une dégradation accrue médiée par le protéasome ainsi qu’une relocalisation cytoplasmique et une modification de l’intégration dans le module kinase CDK8 ont été observées uniquement pour le faux-sens p.Gly1899Arg.Cette étude confirme que les variations faux-sens de MED13L sont une cause du Syndrome MED13L avec des particularités cliniques et moléculaires. Les faux-sens de MED13L associées aux phénotypes typiques (p.Gly1899Arg et p.Thr2162Met) induisent probablement une perte de fonction, tandis que les variations associées aux phénotypes sévères provoqueraient probablement un effet dominant-négatif.
... Copy number variations (CNVs), single-nucleotide variations (SNVs) and indels involving the MED13L gene (mediator complex subunit 13 like -OMIM*608771) can lead to an autosomal dominant clinical condition (mental retardation and distinctive facial features with or without cardiac defects -MRFACD, OMIM#616789) characterised by intellectual disability (ID) associated with facial dysmorphisms in which heart defects have incomplete penetrance (Cafiero et al. 2015;Asadollahi et al. 2017). Both the MED13L haploinsufficiency mutation and missense mutation have been reported to be causative (Yi et al. 2020). ...
... MED13L mutations were related to the clinical condition OMIM#616789 (mental retardation and distinctive facial features with or without cardiac defects) and with several types of genetic variants involving MED13L gene: nonsense (Cafiero et al. 2015;Caro-Llopis et al. 2016), frameshift (Hamdan et al. 2014;Redin et al. 2014;Adegbola et al. 2015;Cafiero et al. 2015;Codina-Solà et al. 2015;Asadollahi et al. 2017;Yamamoto et al. 2017), CNV deletion including MED13L (Adegbola et al. 2015), CNV duplication including MED13L (Adegbola et al. 2015), CNV triplication including MED13L (Asadollahi et al. 2013), intragenic CNV deletion (Asadollahi et al. 2013;Adegbola et al. 2015;van Haelst et al. 2015;Yamamoto et al. 2017), intragenic CNV duplication (Adegbola et al. 2015), disruptive translocation (Muncke et al. 2003;Utami et al. 2014) and missenses (Gilissen et al. 2014;Asadollahi et al. 2017;Yi et al. 2020). In general, they are cases of heterozygous variants. ...
... They also suggest that patients carrying missense variants develop epilepsy earlier, compared with patients with protein-truncating variants (4/9 vs. 1/26). Further, according to Yi et al. (2020), patients with missense mutations in MED13L also have a more severe phenotype in other aspects, including hypotonia, absent speech and severely delayed motor function, compared with patients with truncating variants. The occurrence of truncating variants involving the entire MED13L gene would lead to the conclusion that the clinical condition is due to haploinsufficiency. ...
Background
Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism.
Methods
We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole-exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome.
Results
Two MED13L variants have been identified [MED13L(NM_015335.5):c.4417C>T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs.
Conclusions
The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.
The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.
Background
Research on monogenic forms of autism spectrum disorder (autism) can inform our understanding of genetic contributions to the autism phenotype; yet, there is much to be learned about the pathways from gene to brain structure to behavior. This systematic review summarizes and evaluates research on brain magnetic resonance imaging (MRI) findings in monogenic conditions that have strong association with autism. This will improve understanding of the impact of genetic variability on brain structure and related behavioral traits in autism.
Methods
The search strategy for this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Risk of bias (ROB) assessment was completed on included studies using the Newcastle‐Ottawa Scales.
Results
Of 4,287 studies screened, 69 were included pertaining to 13 of the top 20 genes with the strongest association with autism. The greatest number of studies related to individuals with PTEN variants and autism. Brain MRI abnormalities were reported for 12 of the 13 genes studied, and in 51.7% of participants across all 13 genes, including 100% of participants with ARID1B variants. Specific MRI findings were highly variable, with no clear patterns emerging within or between the 13 genes, although white matter abnormalities were the most common. Few studies reported specific details about methods for acquisition and processing of brain MRI, and descriptors for brain abnormalities were variable. ROB assessment indicated high ROB for all studies, largely due to small sample sizes and lack of comparison groups.
Conclusions
Brain abnormalities are common in this population of individuals, in particular, children; however, a range of different brain abnormalities were reported within and between genes. Directions for future neuroimaging research in monogenic autism are suggested.
