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.
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Authors | Ali R Keramati, Anita Sadeghpour, Maryam M Farahani, Gurangad Chandok, Arya Mani |
Journal | BMC medical genetics
(BMC Med Genet)
Vol. 11
Pg. 143
(Oct 11 2010)
ISSN: 1471-2350 [Electronic] England |
PMID | 20937124
(Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- FBN1 protein, human
- Fibrillin-1
- Fibrillins
- Microfilament Proteins
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Topics |
- Aortic Dissection
(genetics)
- Aortic Aneurysm, Thoracic
(genetics)
- Chromosomes, Human, Pair 15
- Echocardiography
- Fibrillin-1
- Fibrillins
- Genetic Loci
- Genome-Wide Association Study
- Genotype
- Haplotypes
- Humans
- Male
- Marfan Syndrome
(genetics)
- Microfilament Proteins
(genetics)
- Middle Aged
- Odds Ratio
- Pedigree
- Polymorphism, Single Nucleotide
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