Aortic Aneurysm, Familial Thoracic 11, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to familial thoracic aortic aneurysm-11 (AAT11) is caused by heterozygous mutation in the FOXE3 gene (601094) on chromosome 1p33.

For a general phenotypic description and a discussion of genetic heterogeneity of thoracic aortic aneurysm, see AAT1 (607086).

Clinical Features

Kuang et al. (2016) studied a large 4-generation family (family TAA337) in which there were 8 cases of acute aortic dissection inherited in an autosomal dominant manner. The dissections occurred at an average age of 45.6 years (range, 27 to 63 years) in individuals with no history of hypertension. Affected family members presented with acute ascending aortic dissection with dilatation noted at time of surgery; only 1 family member had a descending aortic dissection. There was evidence of decreased penetrance in the family: only men were affected, 1 female obligate carrier died at age 87 years with no aortic disease, and 2 more mutation-positive women were asymptomatic at 23 and 61 years of age. Histologic examination of affected aortic tissue showed that regions of the medial layer had relatively intact elastin lamellae, but loss of smooth muscle cells between the lamellae.

Inheritance

The transmission pattern of AAT11 in the family reported by Kuang et al. (2016) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a large 4-generation family (TAA337) with autosomal dominant thoracic aortic aneurysm and dissection (TAAD), negative for mutation in known TAAD genes, Kuang et al. (2016) performed exome sequencing and identified heterozygosity for a missense mutation within the forkhead DNA-binding domain of the FOXE3 gene (D153H; 601094.0007) that segregated with disease (lod score, 3.0). Analysis of the FOXE3 gene in 564 unrelated probands with TAAD identified 3 additional likely pathogenic rare missense variants within the same domain, including a missense mutation (G137D; 601094.0008) in a father and 2 sons (family MS300) with aortic root dilation. Kuang et al. (2016) concluded that unique FOXE3 mutations within the forkhead domain predispose individuals to TAAD.