PgmNr Z6173: In vivo modeling of copy number variants in Marfan Syndrome and Autosomal Dominant Polycystic Kidney Disease-associated phenotypes.

Authors:
D. Schepers ¹ ; C. Golzio ² ; E. Davis ² ; C. Claes ¹ ; E. Reyniers ¹ ; A. Raes ³ ; N. Katsanis ¹ ; L. Van Laer ¹ ; B. Loeys ¹

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Institutes
1) Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; 2) Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA; 3) Department of Pediatrics, Ghent University, Ghent, Belgium.

Abstract:

Thoracic aortic dissections are among the most life threatening forms of cardiovascular disease. Thoracic aortic aneurysm, preceding dissection, is a prominent clinical feature of several heritable connective tissue disorders, including Marfan syndrome (MFS). MFS is caused by mutations in FBN1, which encodes fibrillin-1, an important extracellular matrix protein. Mutations in PKD1 or PKD2, two polycystin encoding genes, are responsible for autosomal dominant polycystic kidney disease (ADPKD). Aortic and arterial aneurysms also occur in ADPKD. Vice versa, kidney cysts have also been observed in MFS. This clinical overlap suggests a mechanistic link between ADPKD and MFS.

Here we describe a four generation family with nine affected individuals presenting with both thoracic aortic aneurysm and mild cystic kidneys. FBN1, PKD1 and PKD2 were excluded as disease causing genes by linkage analysis and/or sequencing. Subsequently, whole genome linkage analysis resulted in the delineation of a unique linked region on chromosome 16q21-q24.1. Exome sequencing was performed but no putative causal variants were found in the linked region. Copy number variation analysis identified two duplicated regions in the linkage interval, one (chr16: 86862531-870228808) gene-less and the other (chr16: 86357163-86725305) containing seven genes, including three genes encoding transcription factors of the FOX gene family (FOXC2, FOXF1, FOXL1), one gene encoding a methenyl tetrahydrofolate synthetase containing domain protein (MTHFSD) and three long non coding RNAs (LOC732275, FENDRR, FLJ30679). The presence of the first duplication and its segregation in the family was confirmed using Multiplex Amplicon Quantification analysis. By overexpressing these genes separately and in combination with each other in zebrafish, we will explore the pathogenic mechanisms underlying not only MFS and ADPKD, but aneurysm and cyst formation in general. Preliminary results of these experiments, revealing a potential role for FOXF1 in cyst formation, will be presented.

ZFIN Genetics Index
1. foxf1