Iris Flocculi Are an Ocular Marker of Smooth Muscle -Actin (Acta2) Mutation in Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections (TAAD)

Abstract

Purpose: : We recently reported that missense mutations in the smooth muscle α-actin (ACTA2) are responsible for 14% of familial thoracic aortic aneurysms leading to acute aortic dissections (TAAD). The aim of this study was to report the ocular phenotype associated with TAAD resulting from ACTA2 mutation in a 3 generation family from Northern Ireland.

Methods: : All family members had a full ocular examination including slit-lamp photography and high resolution anterior segment non-contact optical coherence tomography (Visante^TM, Carl Zeiss Meditec, Inc.). The examining ophthalmologist was masked to the disease status and the ocular examination was preformed prior to genetic analysis. Following DNA extraction, mutational analysis of ACTA2 (NM_001613) was performed by bidirectional sequencing.

Results: : The proband died aged 37 following an aortic dissection. Four ‘at-risk’ individuals underwent clinical and genetic evaluation. All four individuals had evidence of iris flocculi of varying degrees. High resolution anterior segment OCT demonstrated the cystic nature of the lesions. A heterozygous 492C>T substitution in ACTA2 resulting in a non-conservative amino acid substitution of arginine to cysteine at codon 149 (R149C) was detected in affected individuals and absent from controls. Iris flocculi segregated with the R149C mutation in this family corroborating that iris flocculi are an ocular marker of TAAD. Molecular analysis of the original family in which iris flocculi were reported in 1995 demonstrated segregation of the iris lesions with a R149C mutation in ACTA2.

Conclusions: : Iris flocculi, which are excrescences of the iris pigmentary epithelium at the pupillary margin, segregated with the presence of smooth muscle α-actin (ACTA2) mutation, and are an ocular marker for TAAD. Further studies are required to establish if iris flocculi associated with TAAD are specific to the R149C mutation in ACTA2.

Keywords: genetics • mutations • iris