De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females

Li, Dong; Strong, Alanna; Shen, Karen; Cassiman, David; Dyck, Maria Van; Linhares, Natália Duarte; Valadares, Eugênia Ribeiro; Wang, Tiancheng; Pena, Sérgio Danilo Junho; Jaeken, Jaak; Vergano, Samantha A. Schrier; Zackai, Elaine H.; Hing, Anne V.; Chow, Penny; Ganguly, Arupa; Scholz, Tasja; Bierhals, Tatjana; Deindl, Philipp; Hákonarson, Hákon; Bhoj, Elizabeth

doi:10.1038/s41436-020-01031-7

Cited by 22 publications

(32 citation statements)

References 40 publications

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“…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%

“…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%

“…Protein truncating variants have been found in only two men, and then only in the last amino acid residues at the end or after the PQL domain at the C-terminus [ 20 , 21 ]. Li et al [ 16 ] describe a cohort of seven female patients with Hardikar syndrome, a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation. Hardikar syndrome does not include ID and does not present with other symptoms often associated with MED12-related disorders.…”

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

“…It also regulates the activity of the kinase module via interaction with a conserved T-loop on CDK8 [ 13 ]. Due to the important role of MED12 in the regulation of several developmental and signaling pathways, somatic variants in MED12 are known to be involved in cancer and germline variants cause a spectrum of developmental disorders that involve Hardikar syndrome to relatively unspecific non-syndromic intellectual disability (ID) [ 8 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

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: 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%

Section: Variants In Med12 Cause (Neuro)developmental Disordersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Plassche

Brouwer

2021

Genes

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Exome and RNA‐Seq analyses of an incomplete penetrance variant in USP9X in female‐specific syndromic intellectual disability

March

Wang

et al. 2022

American J of Med Genetics Pt A

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Pathogenic variants in USP9X, on X chromosome, have been implicated in syndromic intellectual disability (ID) in both males and females with distinct craniofacial features.We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID (MIM 300969, also known as MRX99F). To investigate the possible genetic etiology of the reduced penetrance, Xinactivation, RNA-Seq, and full quad exome analyses were attempted, but failed to identify a promising candidate modifier. While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered.

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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 loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females

Cited by 22 publications

References 40 publications

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

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

Exome and RNA‐Seq analyses of an incomplete penetrance variant in USP9X in female‐specific syndromic intellectual disability

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

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