Language and Cognitive Impairment Associated with a Novel p.Cys63Arg Change in the MED13L Transcriptional Regulator

Jiménez-Romero, Ma Salud; Carrasco-Salas, Pilar; Benítez‐Burraco, Antonio

doi:10.1159/000485638

Cited by 10 publications

(8 citation statements)

References 36 publications

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“…• NOTCH1, responsible for Adams Oliver Syndrome, is required for neuronal differentiation, dendrite development and synaptic plasticity in developing brain [64][65][66] . • Similarly, subjects with haplo-insufficiently of MED13L show ID and severe speech delay; congenital heart defects are found in 20-50% of patients 79,81 . In preclinical studies, haploinsufficiency of MED13L shows defects in both neuronal migration and differentiation 82,83 .…”

Section: Genementioning

confidence: 97%

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Ji¹,

Ferdman²,

Copel³

et al. 2020

Sci Rep

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congenital heart disease (cHD) survivors are at risk for neurodevelopmental disability (nDD), and recent studies identify genes associated with both disorders, suggesting that nDD in cHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that nDD in cHD may be attributable to genes altering both neural connectivity and cardiac patterning. to assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. cHD cases had more protein truncating and deleterious missense DnVs among connectome genes compared to controls (oR = 5.08, 95%CI:2.81-9.20, Fisher's exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02-6.73, Fisher's exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11,

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Section: Genementioning

confidence: 97%

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Ji¹,

Ferdman²,

Copel³

et al. 2020

Sci Rep

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“…MRFACD, MED13L -related intellectual disability syndrome, a recently recognized but well-described congenital malformation, is an intellectual disability syndrome with detailed clinical descriptions available for only 75 reported individuals ( Muncke et al 2003 ; Asadollahi et al 2013 , 2017 ; Redin et al 2014 ; Utami et al 2014 ; Adegbola et al 2015 ; Cafiero et al 2015 ; van Haelst et al 2015 ; Caro-Llopis et al 2016 ; Yamamoto et al 2017 ; Gordon et al 2018 ; Jiménez-Romero et al 2018 ; Smol et al 2018 ; Tørring et al 2019 ; Yi et al 2020 ; Dawidziuk et al 2021 ). A further 14 cases have been identified in the frames of large high-throughput sequencing studies investigating the genetic background of intellectual disability or congenital heart defect ( Musante et al 2004 ; Najmabadi et al 2011 ; Iossifov et al 2012 ; Hamdan et al 2014 ; Iglesias et al 2014 ; Codina-Solà et al 2015 ; Martínez et al 2017; Mullegama et al 2017 ; Aoi et al 2019 ; Ji et al 2020 ; Sabo et al 2020 ; Tian et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

MED13L-related intellectual disability due to paternal germinal mosaicism

Bessenyei

Balogh

Mokánszki

et al. 2021

Cold Spring Harb Mol Case Stud

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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.

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“…However, the clinical relevance of missense mutations in MED13L is poorly understood, and only a limited number of patients have been described (Jiménez‐Romero et al . 2018; Smol et al . 2018).…”

Section: Literature Review and Discussionmentioning

confidence: 99%

Two novel pathogenic variants in MED13L: one familial and one isolated case

Carvalho

Costa

Campagnari³

et al. 2021

J intellect Disabil Res

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BackgroundGenetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism.MethodsWe 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.ResultsTwo 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.ConclusionsThe 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.

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Language and Cognitive Impairment Associated with a Novel p.Cys63Arg Change in the MED13L Transcriptional Regulator

Cited by 10 publications

References 36 publications

De novo damaging variants associated with congenital heart diseases contribute to the connectome

De novo damaging variants associated with congenital heart diseases contribute to the connectome

MED13L-related intellectual disability due to paternal germinal mosaicism

Two novel pathogenic variants in MED13L: one familial and one isolated case

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