Is MED13L-related intellectual disability a recognizable syndrome?

Tørring, Pernille Mathiesen; Larsen, Martin Jakob; Brasch‐Andersen, Charlotte; Krogh, Lotte Nylandsted; Kibæk, Maria; Laulund, Lone Walentin; Illum, Niels Ove; Dunkhase-Heinl, Ulrike; Wiesener, Antje; Popp, Bernt; Marangi, Giuseppe; Hjortshøj, Tina Duelund; Ek, Jakob; Vogel, Ida; Becher, Naja; Roos, Laura; Zollino, Marcella; Fagerberg, Christina

doi:10.1016/j.ejmg.2018.06.014

Cited by 25 publications

(25 citation statements)

References 26 publications

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“…To date, 69 patients carrying de novo MED13L variants have been described (35 females, 34 males) [ 47 ]. All of these patients showed ID and developmental delay, and other aspects of the phenotypic spectrum of MED12 -related disorders were also found, but to a lesser degree ( Table 1 ).…”

Section: The Pathogenic Variants In Other Kinase Unit Proteins Cause a Similar Phenotypementioning

confidence: 99%

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Plassche

Brouwer

2021

Genes

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MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

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Section: The Pathogenic Variants In Other Kinase Unit Proteins Cause a Similar Phenotypementioning

confidence: 99%

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Plassche

Brouwer

2021

Genes

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“…By reviewing the literature, we found 17 missense mutations in 20 patients [ 2 , 11 – 19 ]. Compared with the overall incidence in all MED13L-related patients summarized by Torring et al and Smol et al, patients with missense mutations have a higher incidence of seizures (44.4% vs 16%), MRI abnormalities (66.7% vs 45%) and autistic features (55.6% vs 23%) [ 11 , 12 ]. The incidence of ID and hypotonia was similar to the overall incidence, but the phenotypes were much more serious.…”

Section: Discussionmentioning

confidence: 99%

“…The incidence of ID and hypotonia was similar to the overall incidence, but the phenotypes were much more serious. The incidence of cardiac anomalies was slightly higher than the overall incidence (27.8% vs 19%) [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Independently, Musante et al cloned the gene by RT-PCR and 5-prime RACE of human fetal brain and lymphoblastoid cell line cDNA libraries, which they called THRAP2 [ 3 ]. A decade later, an increasing number of cases harboring large intragenic or whole gene deletions/duplications of the MED13L gene, chromosomal translocation disrupting the MED13L gene, de novo frameshift variants, nonsense mutations, and splice site mutations were published, exhibiting moderate ID, severe speech impairment, motor developmental delay, facial deformity and/or CHD, and these were recognized as MED13L haploinsufficiency syndrome [ 4 – 11 ]. Several missense mutations in the MED13L gene have also been reported and are supposed to frequently have a more severe phenotype with hypotonia, more frequently epilepsy, severe absent speech, and severely delayed motor function compared to patients with truncating variants [ 11 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability

Zhang

Song

et al. 2020

Ital J Pediatr

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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 missense mutations have more frequent epilepsy and show a more severe phenotype. Case presentation We report a child with ID, speech impairment, severe motor developmental delay, facial deformity, hypotonia, muscular atrophy, scoliosis, odontoprisis, abnormal electroencephalogram (EEG), and congenital ureteropelvic junction obstruction (UPJO) combined with high ureter attachment. We used whole-exome sequencing (WES) to detect the genetic aberration of the child and found a de novo mutation, c.2605C > T (p.Pro869Ser), in the MED13L gene. Neither of her parents carried the mutation. Additionally, we review the literature and summarize the phenotypes and features of reported missense mutations. After reviewing the literature, approximately 17 missense mutations in 20 patients have been reported thus far. For 18 patients (including our case) whose clinical manifestations were provided, 100% of the patients had ID or developmental delay (DD). A total of 88.9, 83.3 and 66.7% of the patients had speech impairment, delayed milestones and hypotonia, respectively. A total of 83.3% of the patients exhibited craniofacial deformity or other dysmorphic features. Behavioral difficulties and autistic features were observed in 55.6% of the patients. Cardiac anomalies were seen in only 27.8% of the patients. Of these patients, 44.4% had epileptic seizures. Of the 17 mutations, 2 were located in the N-terminal domain, 8 were located in the C-terminal domain, and 1 was located in an α-helical sequence stretch. One of them was located in the MID domain of the MedPIWI module. Conclusions We report a new patient with a reported missense mutation, c.2605C > T (p.Pro869Ser), who exhibited some infrequent manifestations except common phenotypes, which may broaden the known clinical spectrum. Additionally, by reviewing the literature, we also found that patients with missense mutations have a higher incidence of seizures, MRI abnormalities, autistic features and cardiac anomalies. They also have more severe ID and hypotonia. Our case further demonstrates that Pro869Ser is a hotspot mutation of the MED13L gene.

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“…Some MED13 gene mutations are reportedly associated with abnormal heart development [25,26], neurodevelopmental disorders, nervous system disorders, craniofacial dysmorphisms, and muscle diseases [23,27,28] (Table 1). MED13L gene mutations are also associated with these phenotypes, but with more variable features [13,26,[29][30][31][32][33][34][35][36]. MED13 not only plays a critical role in necessary physiological processes, including organismal growth and development, but is also involved in pathophysiological processes and diseases.…”

Section: Ivyspringmentioning

confidence: 99%

Potential roles of mediator Complex Subunit 13 in Cardiac Diseases

Zhou

Cai

et al. 2021

Int. J. Biol. Sci.

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Mediator complex subunit 13 (MED13, previously known as THRAP1 and TRAP240) is a subunit of the cyclin-dependent kinase 8 (CDK8) kinase module in the eukaryotic mediator complex. MED13 has been known to play critical roles in cell cycle, development, and growth. The purpose of this review is to comprehensively discuss its newly identified potential roles in myocardial energy metabolism and non-metabolic cardiovascular diseases. Evidence indicates that cardiac MED13 mainly participates in the regulation of nuclear receptor signaling, which drives the transcription of genes involved in modulating cardiac and systemic energy homeostasis. MED13 is also associated with several pathological conditions, such as metabolic syndrome and thyroid disease-associated heart failure. Therefore, MED13 constitutes a potential therapeutic target for the regulation of metabolic disorders and other cardiovascular diseases.

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Is MED13L-related intellectual disability a recognizable syndrome?

Cited by 25 publications

References 26 publications

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability

Potential roles of mediator Complex Subunit 13 in Cardiac Diseases

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