Further confirmation of the MED13L haploinsufficiency syndrome

Abstract

MED13L haploinsufficiency syndrome has been described in two patients and is characterized by moderate intellectual disability (ID), conotruncal heart defects, facial abnormalities and hypotonia. Missense mutations in MED13L are linked to transposition of the great arteries and non-syndromal intellectual disability. Here we describe two novel patients with de novo MED13L aberrations. The first patient has a de novo mutation in the splice acceptor site of exon 5 of MED13L. cDNA analysis showed this mutation results in an in-frame deletion, removing 15 amino acids in middle of the conserved MED13L N-terminal domain. The second patient carries a de novo deletion of exons 6-20 of MED13L. Both patients show features of the MED13L haploinsufficiency syndrome, except for the heart defects, thus further confirming the existence of the MED13L haploinsufficiency syndrome.

Figure 1

Facial features of patient 1 and 2 with MED13L aberrations: (a) patient 1 at 6 months and (b) 17 months of age. Note macroglossia, facial asymmetry, upslanting palpebral fissures, flat nasal bridge and dark circles under eyes. (c and d) Patient 2 at age 4½ years: slightly different phenotype: note broad nasal bridge, open mouth appearance.

Figure 2

MED13L abberations. (a) Genomic structure of human MED13L with indicated de novo splice site mutation in patient 1 and the minimal de novo deletion of patient 2. (b) Agarose gel results of a PCR on cDNA with primers located on exons 4 and 7. Pt1 denotes cDNA from patient 1 and Ctrl cDNA from a control cDNA sample. The cDNA PCR of patient 1 shows an additional lower band (indicated by arrow). The predicted size of the wildtype band is 467 bp. Sanger sequencing of the band proved an in-frame partial deletion of exon 5. (c) Protein structure of human MED13L, with the conserved protein domains indicated. The splice site mutation in patient 1 results in a deletion of 15 amino acids (160–174) in the conserved MED13L N-terminal domain. The minimal deleted region of patient 2 encompasses exons 6–20 in the middle of the MED13L protein.