De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females

Polla, Daniel L.; Bhoj, Elizabeth; Verheij, Joanne; Wassink-Ruiter, Jolien S. Klein; Reis, André; Deshpande, Charu; Gregor, Anne; Hill-Karfe, K.; Silfhout, Anneke T. Vulto-van; Pfundt, Rolph; Bongers, Ernie M.H.F.; Hákonarson, Hákon; Berland, Siren; Gradek, Gyri Aasland; Banka, Siddharth; Chandler, Kate; Gompertz, Lianne; Huffels, S. C.; Stumpel, Constance T. R. M.; Wennekes, R.; Stegmann, Alexander P.A.; Reardon, William; Leenders, Erika; Vries, Bert B.A. de; Li, D.; Zackai, Elaine H.; Ragge, Nicola; Lynch, Sally Ann; Cuddapah, Sanmati; Bokhoven, Hans van; Brouwer, Arjan P.M. de

doi:10.1038/s41436-020-01040-6

Cited by 22 publications

(36 citation statements)

References 38 publications

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“…All patients had a protein truncating variant and presented with symptoms fitting the spectrum expected for variants in MED12 (Table 1). The three female patients carried variants that were predicted to result in a premature stop codon in the C-terminal part of the protein, as was also observed in several of the patients described by Polla et al [17]. As the MED12 C-terminal region is conserved between MED12L and MED12, this finding can be seen as independently confirming the causal effect of the variants described by Polla et al [17].…”

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

confidence: 78%

“…The missense variants responsible for these disorders are located throughout MED12 and cannot be found in one specific protein domain or motif (Figure 2). [16] and supplemented with data from [17]. Descriptions of individual patients can be found in Table S1.…”

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

“…MED12 is located on Xq13.1. Most patients are male who have inherited the missense variant from a unaffected carrier female ( Table S1 ) [ 17 ]. Several X-linked developmental syndromes are associated with hemizygous MED12 variants, including Opitz–Kaveggia syndrome (FG syndrome, MIM 305450), Lujan–Fryns syndrome (MIM 309520), and X-linked Ohdo syndrome (MIM 300895), as well as non-syndromic X-linked ID [ 18 ].…”

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

“…Recently, females with MED12 variants were identified as well [ 16 , 17 ]. Remarkably, besides missense variants, nonsense and frameshift variants were found.…”

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

“…The MED12 domain that is part of the kinase section of Mediator, the LCEWAV domain with no known function, and the catenin-binding PQL domain are indicated. Only domains predicted by the PFAM database (https://pfam.xfam.org/ (accessed on 1 April 2021) were included in this figure.Figure was adapted from[16] and supplemented with data from[17]. Descriptions of individual patients can be found in TableS1.…”

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confidence: 99%

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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 Phenotypesupporting

confidence: 78%

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

“…Recently, females with MED12 variants were identified as well [ 16 , 17 ]. Remarkably, besides missense variants, nonsense and frameshift variants were found.…”

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

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confidence: 99%

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

Plassche

Brouwer

2021

Genes

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Two females with distinct de novo missense pathogenic variants in MED12 and vastly differing phenotypes

Garcia

Kapur

Walsh

et al. 2021

American J of Med Genetics Pt A

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The MED12 gene has an important role in neuronal gene silencing (Ding et al., 2008;Graham Jr & Schwartz, 2013) and has been associated with four distinct X-linked intellectual disability (ID) conditions: FG syndrome, Lujan syndrome, Ohdo syndrome, and nonspecific ID. Its gene product is part of the large Mediator complex comprised of 31 subunits arranged in four modules that interacts with RNA polymerase II and plays a critical role in regulating transcription (Yin & Wang, 2014). The complex is involved in cell growth, development, and differentiation through epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation, and super enhancer formation (Graham Jr & Schwartz, 2013).

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MED12‐related Hardikar syndrome: Two additional cases and novel phenotypic features

Pillai

Miller

Bronken

et al. 2022

American J of Med Genetics Pt A

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Hardikar syndrome (HS) is a MED12‐related ultra‐rare multiple congenital malformation syndrome known to affect the gastrointestinal, cardiac, and genitourinary systems among other features including cleft lip/palate and pigmentary retinopathy. Only 10 patients affected with HS have been previously described in literature, of which seven were molecularly confirmed. We report a 20‐year‐old and a 13‐month‐old patient with HS diagnosed by exome sequencing bringing the total number of clinically diagnosed cases to 12 and MED12 associated to 9. We describe previously unreported molecular and clinical findings associated with HS and review all reported cases to permit prompt diagnosis, appropriate management, and genetic counseling of HS patients.

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De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females

Cited by 22 publications

References 38 publications

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

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

Two females with distinct de novo missense pathogenic variants in MED12 and vastly differing phenotypes

MED12‐related Hardikar syndrome: Two additional cases and novel phenotypic features

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