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.
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Acknowledgements
We sincerely thank the affected individuals and their families for participation and their permission to publish the results. We are grateful to Dr Cédric Le Caignec (Service de Génétique Médicale, Nantes, France) and Dr Björn Menten (Centrum Medische Genetica, Ghent, Belgium) for accepting the citation of their DECIPHER Consortium cases (numbers 255109 and 257915, respectively) in our discussion. We also thank the DECIPHER Consortium. This research was supported by grants from the Swiss National Science Foundation (SNF 320030_135669) and the Forschungskredit of the University of Zurich, grant number 54220201.
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Asadollahi, R., Oneda, B., Sheth, F. et al. Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability. Eur J Hum Genet 21, 1100–1104 (2013). https://doi.org/10.1038/ejhg.2013.17
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DOI: https://doi.org/10.1038/ejhg.2013.17
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