title: 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.
authors: Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors: Reza
authors: R
authors: Asadollahi
authors: Beatrice
authors: B
authors: Oneda
authors: Frenny
authors: F
authors: Sheth
authors: Silvia
authors: S
authors: Azzarello-Burri
authors: Rosa
authors: R
authors: Baldinger
authors: Pascal
authors: P
authors: Joset
authors: Beatrice
authors: B
authors: Latal
authors: Walter
authors: W
authors: Knirsch
authors: Soaham
authors: S
authors: Desai
authors: Alessandra
authors: A
authors: Baumer
authors: Gunnar
authors: G
authors: Houge
authors: Joris
authors: J
authors: Andrieux
authors: Anita
authors: A
authors: Rauch
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D057895:Haploinsufficiency; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome
chemical_list: C480067:MED13L protein, human; D056892:Mediator Complex
references: Clin Dysmorphol. 2006 Jul;15(3):133-137
references: 16760730
references: Dev Biol. 2007 Aug 15;308(2):322-30
references: 17585897
references: Am J Med Genet A. 2012 Feb;158A(2):400-5
references: 22162340
references: Neurogenetics. 2009 Oct;10(4):275-87
references: 19290556
references: J Biol Chem. 2004 Jul 9;279(28):29270-7
references: 15073178
references: Oncogene. 2012 Nov 1;31(44):4709-17
references: 22249253
references: Curr Opin Genet Dev. 2011 Apr;21(2):225-30
references: 21330129
references: Gene. 2004 May 12;332:119-27
references: 15145061
references: EMBO J. 2002 Jul 1;21(13):3464-75
references: 12093747
references: Nat Genet. 2007 Apr;39(4):451-3
references: 17334363
references: Development. 2003 Aug;130(16):3691-701
references: 12835386
references: Am J Hum Genet. 2005 May;76(5):865-76
references: 15800846
references: Development. 2005 Apr;132(8):1885-93
references: 15790964
references: Dev Dyn. 2011 Sep;240(9):2051-9
references: 21793099
references: Am J Hum Genet. 2007 Jan;80(1):91-104
references: 17160897
references: Development. 2009 Sep;136(18):3173-83
references: 19700621
references: Cell Mol Life Sci. 2012 Nov;69(22):3715-37
references: 22547091
references: J Med Genet. 2007 Jul;44(7):472-7
references: 17369503
references: Science. 2011 Aug 26;333(6046):1161-3
references: 21868677
references: Am J Med Genet A. 2005 Dec 15;139(3):186-93
references: 16283673
references: Am J Hum Genet. 2010 Nov 12;87(5):667-70
references: 20950787
references: Mol Cell. 2004 Jun 4;14(5):685-91
references: 15175163
references: Nature. 2011 Sep 21;478(7367):57-63
references: 21937992
references: Circulation. 2003 Dec 9;108(23):2843-50
references: 14638541