| Summary: | <p>Abstract</p> <p>Background</p> <p>Thoracic aortic aneurysms and dissections (TAAD) is a critical condition that often goes undiagnosed with fatal consequences. While majority of the cases are sporadic, more than 20% are inherited as a single gene disorder. The most common familial TAA is Marfan syndrome (MFS), which is primarily caused by mutations in <it>fibrillin-1 </it>(<it>FBN1</it>) gene. Patients with <it>FBN1 </it>mutations are at higher risk for dissection compared to other patients with similar size aneurysms.</p> <p>Methods</p> <p>Fifteen family members were genotyped using Affymetrix-10K genechips. A genome-wide association study was carried out using an autosomal dominant model of inheritance with incomplete penetrance. Mutation screening of all exons and exon-intron boundaries of <it>FBN1 </it>gene which reside near the peak Lod score was carried out by direct sequencing.</p> <p>Results</p> <p>The index case presented with agonizing substernal pain and was found to have TAAD by transthoracic echocardiogram. The family history was significant for 3 first degree relatives with TAA. Nine additional family members were diagnosed with TAA by echocardiography examinations. The affected individuals had no syndromic features. A genome-wide analysis of linkage mapped the disease gene to a single locus on chromosome 15q21 with a peak Lod score of 3.6 at <it>fibrillin-1 </it>(<it>FBN1</it>) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that <it>FBN1 </it>is the causative gene. No mutation was identified within the exons and exon-intron boundaries of <it>FBN1 </it>gene that segregated with the disease. Haplotype analysis identified additional mutation carriers who had previously unknown status due to borderline dilation of the ascending aorta.</p> <p>Conclusions</p> <p>A familial non-syndromic TAAD is strongly associated with the <it>FBN1 </it>gene locus and has a malignant disease course often seen in MFS patients. This finding indicates the importance of obtaining detailed family history and echocardiographic screening of extended relatives of patients with non-syndromic TAAD to improve the outcome. In addition, association of non-syndromic TAAD with the Marfan disease gene locus poses the question whether secondary prevention strategies employed for Marfan syndrome patients should be applied to all patients with familial TAAD.</p>
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