Modelling Of Double Hit Mutations In Thoracic Aortic Aneurysm Disease That Have Variable Impact On Phenotype

Multiple genes are associated with thoracic aortic aneurysm (TAA) formation, including FBN1, TGFBR1u00262, COL3A1 u0026 5A2, and MYH11. We hypothesized that given the population incidence of mutations in these genes it is likely that ‘double-hit’ mutations occur, which may result in an altered clinical phenotype when compared with the single gene mutation.Genomic DNA analysis of 16 genes implicated in TAA was performed on 11 patients with inherited TAA disease. Of the patients analysed, one patient (P1) was identified as having a mutation in both MYH11 (c.2517G.C (pW839C)) and FBN1 (splice donor site c.4210+1Gu003eA). Another patient (P2) was identified as having both COL5A2 (c.3794Au003eG (pD1265G)) and FBN1 (c.5861Tu003eG (p.F1954C)). All mutations were predicted by PolyPhen to be deleterious.P1 has Marfan Syndrome (MFS), caused by the FBN1 mutation, and has severe aortic dilatation while his mother (M1), who also has MFS but does not have the MHY11 mutation, developed mild aortic dilatation, suggesting that the MHY11 mutation in P1 has resulted in a more aggressive phenotype.P2, siblings S1 and S2 and father (F2) all have relatively less severe MFS with progressive moderate dilatation of the aorta. Thus, the phenotype of pedigree 2 is similar for all affected members, but only P2 has a double-hit mutation, suggesting that the presence of the COL5A2 mutation in P2 has not altered the clinical phenotype.The potential contribution of these mutations to phenotype using molecular modelling will be presented. This is the first instance where double-hit mutations have been described in familial TAA but the effect of multiple mutations on phenotype appears to be variable. Mutation analysis for individuals with familial TAA should look beyond the identification of a single gene culprit.