Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Abstract

A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.

Figure 1

Facial features of patients 1 and 2 with MED13L haploinsufficiency. (a, b) patient 1 at 13 months and, (c) at 4.5 years of age. Note broad forehead with bitemporal narrowing, mild facial asymmetry, long eyelashes and upslanting palpebral fissures, flat nasal root, bulbous nose, deep philtrum and macroglossia. (d, e and f) patient 2 at 2 years and 9 months of age with notable similarity in facial gestalt.

Figure 2

Copy number variants of MED13L in our patients. Patient 1 (DECIPHER no. 265241) with a de novo deletion of exon 2 (red bar), patient 2 (DECIPHER no. 260584) with a de novo deletion encompassing exons 3 and 4 (red bar) and patient 3 with a de novo triplication of the region 114  508 443–115 527 724 (Homosapiens, build 36/hg18) (blue bar), which includes the whole MED13L gene, several non-protein-coding RNA genes and MAP1LC3B2. Patients 255 109 and 257 915 are from the DECIPHER database with 60 kbp de novo gain within exons 5–28 of MED13L and 120 kbp de novo loss within its exons 3 and 4, respectively (https://decipher.sanger.ac.uk). Variation_4787 from the Database of Genomic Variants (build 36) (http://projects.tcag.ca/variation, build 36) is shown in the upper part. Variation_4787, a 173 kbp deletion observed in 6 out of 95 controls using BAC Array CGH, is likely a false-positive finding due to a misbehaving BAC. This variation was not observed in our 820 control individuals.