The Phenotypic-to-Genotypic Association of Novel Single-Nucleotide Polymorphisms in the Collagen Matrix-Encoding Gene ZNF469 in Arterial Aneurysmal Diseases

Abstract

Research Question: In patients with a strong personal and or family history of aortic and or aneurysmal events, in the absence of known syndromic mutations, is there be a genetic basis for disease?

Background, Significance, and Rationale: Aneurysms and dissections are devastating vascular pathologies which are increasingly recognized to have a genetic basis. In this report we share novel mutations in ZNF469 in eight patients in our practice with vasculopathy, such as aneurysm, ectasia, and/or dissections. This gene is responsible for the production of a collagen-related zinc-finger protein involved in multiple aspects of the development and regulation of major extracellular matrix components. Methods: Patients with significant personal or familial history of aneurysmal or dissection diseases were genotyped to assess mutation status of genes associated with vasculature, extracellular matrix, and aneurysmal/dissection disease.

Results: All patients were positive for ZNF469 mutations, with 7/8 being positive for variants of unknown significance, and 1/8 positive for a pathologic mutation indicated in development of brittle cornea syndrome. Of the eight patients tested, 5/8 (62.5%) have ectasia/aneurysmal disease, 3/8 (37.5%) have experienced vascular dissection, and 4/8 (50.0%) have a family history of 1 or more first-degree relative with aneurysmal or dissection disease.

Conclusions: We recently reported the first known case associating this genotype to phenotype, and this work significantly extends this discovery by associating polymorphisms in this gene with vasculopathies in a significant cohort of unrelated patients. Furthermore, the co-segregation of these mutations exclusively within exon 1 and exon 2 of this gene suggests the importance of these exons in the genetic architecture of ZNF469 as it relates to human disease.