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.

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

“…5,6 With respect to the SYT1 mutation, elements supporting its pathogenicity are the following: de novo origin; it has never been reported in control populations (dbSNPs, EVS and 1000genomes databases); non-synonymous variants across the whole gene are very rare in general population (only a single SNP with MAF slightly 41%); the substitution is predicted to be 'damaging' by the SIFT online tool (J. Craig Venter Institute, Rockville, MD, USA) and 'deleterious' with a probability of 0.75 by the PANTHER evolutionary analysis of coding SNPs (even though PolyPhen-2 prediction is 'benign'); it involves an important functional domain of SYT1; and SYT1 (synaptotagmin 1, OMIM: 185605) encodes a presynaptic protein, necessary for signal transmission across synapses. 11,12 The detected gene variants were submitted to LOVD database (http://databases.lovd.nl/shared/genes/MED13L).…”

“…We report on the first three frameshift/nonsense variants in MED13L, since partial gene deletions, splice-site variant likely resulting in in-frame deletions, 5,6 and missense variants 7 had been previously reported in the literature.…”

“…A comprehensive analysis of our patients and literature patients as well allowed us to reinforce the consideration that a common phenotype exists in association with haploinsufficiency of the gene, as already suggested. 5,6 Our patients 1 and 2 presented with an overlapping phenotype characterized by moderate ID, hypotonia, distinctive facial features, including brachycephaly, horizontal eyebrows, high forehead, bitemporal narrowing, long eyelashes, depressed nasal bridge, mid-face hypoplasia, prognathism and friendly behavior. Additional clinical features included cleft palate, clubfoot and conductive hearing loss in patient 1; seizures, microcephaly and atrial septal defect in patient 2.…”

“…8 Only recently, it was demonstrated that MED13L is a dosage-sensitive gene and a clinically recognizable phenotype exists, caused by its haploinsufficiency. 5,6 By means of array-CGH, Asadollahi et al 5 detected a heterozygous partial gene deletion in two patients with ID, phenotypic anomalies and various CHDs, other than dTGA. Another heterozygous partial gene deletion detected by array-CGH has been subsequently reported by van Haelst et al, 6 along with one heterozygous splice-site variant detected by WES in association with ID, facial dysmorphism, hypotonia, but with no conotruncal heart defects.…”

“…MED13L haploinsufficiency, as a consequence of gene deletions and loss-of-function intragenic variants, was recently delineated to cause a recognizable ID syndrome with or without congenital heart defects (CHDs). 5,6 On the contrary the clinical relevance of missense variants within the MED13L gene is still poorly understood. In 2003, Muncke et al 7 suggested association of missense variants in this gene with isolated CHDs.…”