Recessively Inherited Severe Aortic Aneurysm Caused by Mutated EFEMP2

Familial aortic aneurysm (AA) is mostly inherited as an autosomal dominant disorder. However, recessively inherited AA has also been observed but in association with skin manifestations of cutis laxa, which is caused by a mutated EFEMP2 gene. In the present study, we recruited 9 patients, from 4 unrelated consanguineous families, with recessively inherited AA. The index cases, their parents, and siblings underwent clinical evaluation and cardiac imaging. In the affected subjects, the clinical presentation ranged from sweating and cyanosis at 3 months of age to incidental findings in an asymptomatic adult. The echocardiogram revealed a wide spectrum of severity of the AA, with a Z-score varying from 5 to 33. Intrafamilial variability was also evident; 2 unrelated subjects were detected at 17 and 20 years of age through family screening. The skin manifestations of cutis laxa were not found in any patient. In 1 family, genome-wide single-nucleotide polymorphism analysis detected a homozygous block, shared by 2 affected siblings, on chromosome 11 at q13. Sequence analysis of EFEMP2, located on chromosome 11 at q13, identified a novel homozygous mutation (p.E161K) in all 9 affected subjects. In this largest cohort of reported patients with a mutated EFEMP2 gene, we illustrate the phenotypic spectrum of inherited AA due to a novel EFEMP2 mutation. In conclusion, our work suggests that in families with apparently recessively inherited AA, molecular analysis of EFEMP2 gene might be warranted.