The non-syndromic familial thoracic aortic aneurysms and dissections maps to 15q21 locus

Abstract

Background: 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 fibrillin-1 (FBN1) gene. Patients with FBN1 mutations are at higher risk for dissection compared to other patients with similar size aneurysms.

Methods: 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 FBN1 gene which reside near the peak Lod score was carried out by direct sequencing.

Results: 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 fibrillin-1 (FBN1) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that FBN1 is the causative gene. No mutation was identified within the exons and exon-intron boundaries of FBN1 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.

Conclusions: A familial non-syndromic TAAD is strongly associated with the FBN1 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.

Figure 1

Ascending aortic dissection. Transthoracic echocardiogram in index case depicting dissection in proximal ascending aorta.

Figure 2

Echocardiography image-aneurysm. A left parasternal view of the ascending aorta in echocardiography examination of an affected family member with an aneurysm radius of 3.8.

Figure 3

TAAD pedigree. Relationships of members of kindred with TAAD are shown. The index case is indicated by the arrow. Numbered individuals correspond to those in Additional File 1. Individuals with TAA are indicated by black symbols; individuals without TAA are shown as unfilled symbols; and individuals who have unknown status are shown as half-gray symbols. Circles represent females; squares represent males. Symbols with a slash through them indicate deceased subjects. Genotypes of informative SNP markers are shown in their chromosomal order below the symbol for each individual and their distances from 15pter are indicated in megabases.

Figure 4

Lod Score. Multipoint lod scores for linkage of TAAD to 15q21. SNPs tightly linked to the location of the maximum lod score are indicated and the location of FBN1 is shown. The lod score peak occurs at zero recombination with marker rs1876206. y-Axis, LOD score; x-axis, position of the markers on chromosome 15q, based on their relative chromosomal distance. Position of the markers is given in centiMorgans (cM).