MED13L haploinsufficiency syndrome: A de novo frameshift and recurrent intragenic deletions due to parental mosaicism

Abstract

MED13L haploinsufficiency syndrome is a clinical condition manifesting intellectual disability and developmental delay in association with various complications including congenital heart defects and dysmorphic features. Most of the previously reported patients showed de novo loss-of-function mutations in MED13L. Additional three patients with MED13L haploinsufficiency syndrome were identified here in association with rare complications. One patient had a de novo deletion (c.257delT) and T2-weighted high intensity in the occipital white matter on magnetic resonance imaging. Two siblings exhibited an intragenic deletion involving exons 3-14, which led to an in-frame deletion in MED13L. The deletion was inherited from their carrier mother who possessed low frequency mosaicism. The older sister of the siblings showed craniosynostosis; this condition has never been reported in patients with MED13L haploinsufficiency syndrome. Dysmorphic features were observed in these patients; however, most of the findings were nonspecific. Further information would be necessary to understand this clinical condition better.

Analysis of Polymorphisms in the Mediator Complex Subunit 13-like (Med13L) Gene in the Context of Immune Function and Development of Experimental Arthritis

“…Mutations in the MED13L gene have established causation of transposition of the great arteries, a congenital heart anomaly (Adegbola et al 2015 ; Lei et al 2014 ). More recently, a wider spectrum of diseases has been linked to genetic variations in this gene and are collectively termed as MED13L haploinsufficiency syndrome, which is characterized by cardiac anomalies, developmental delay, distinctive facial features, intellectual disability, and in some cases craniosynostosis (Adegbola et al 2015 ; Yamamoto et al 2017 ). However, presentation of the MED13L haploinsufficiency syndrome varies among affected individuals, and not all patients have the associated cardiac phenotype (van Haelst et al 2015 ).…”

“…To date, 22 disease-associated mutations have been reported in the MED13L gene, but the molecular pathways affected by these mutations, leading to the reported clinical phenotypes, are largely unknown (Musante et al 2004 ; Yamamoto et al 2017 ). MED13L has been reported to be involved in the Wnt, fibroblast growth factor (FGF), and retinoblastoma (Rb)/E2F pathways (Angus and Nevins 2012 ; Asadollahi et al 2017 ; Utami et al 2014 ).…”

Novel A178P mutation in SLC16A2 in a patient with Allan‐Herndon‐Dudley syndrome

“…After receiving written informed consent from the patient's family, we obtained blood samples from the family members and extracted genomic DNA. Clinical exome sequencing was performed using the TruSight One v1.0 sequencing panel (Illumina, San Diego, CA, USA), as previously described (Yamamoto et al ). The extracted data were mapped to the GRCh37/hg19 reference genome, and annotated and filtered using the Variant Studio software (Illumina).…”

MED13L loss‐of‐function variants in two patients with syndromic Pierre Robin sequence

“…MED13L alterations and their associated phenotypes have been recently summarized for 25 patients (Yamamoto et al, ). A further 19 patients with de novo MED13L mutations were identified in an exome sequencing study of a large cohort of patients with developmental disorders (McRae et al, ).…”

“…MED13L encodes a component of the CDK8 module of the Mediator complex, which regulates transcription via interactions between upstream transcription factors and the basal RNA polymerase II initiation machinery (Malik & Roeder, ). Variable phenotypes have hitherto been ascribed to MED13L gene mutations, with intellectual disability (ID), hypotonia, marked speech delay, motor delay, and a characteristic facial appearance (upslanted palpebral fissures, broad nasal tip and an open‐mouthed posture, often with a wide mouth) emerging as key features (Adegbola et al, ; Cafiero et al, ; Yamamoto, Shimojima, Ondo, Shimakawa, & Okamoto, ). With this report, we expand the phenotype of MED13L –related disorders to include PRS.…”