Acute Aortic Disease.. - Index of

108 Milewicz et al.
dissection in the descending aorta, abdominal aorta, cerebral vasculature, carotid
arteries, and peripheral arteries. Many of the TAAD families have congenital
cardiac features in one or more members as documented by echocardiogram or
surgical repair, including bicuspid aortic valve (BAV), patent ductus arteriosus
(PDA), and septal defects (ASD or VSD) (42,43).
Analysis of the inheritance of TAAD in the families collected indicates that
the predisposition to develop TAADs is inherited in these families as mutations in
a single gene and the phenotype has a variable age of onset and clinical presentation.
In addition, decreased penetrance is evident, especially in the women in
these families, that is, inheritance of the defective gene did not always result in
aortic disease. Genetic mapping is an approach used to determine the location of
the gene responsible for an inherited single-gene disorder in the human genome.
Linkage describes the phenomenon that genetic markers, which are located near
the defective gene causing the disease, will segregate with the disease phenotype
in a family. Microsatellites and single nucleotide polymorphisms (SNPs) are the
two most common genetic markers used for genetic mapping. A microsatellite
marker is a short tandem repeat polymorphism and each repeat unit contains
two to four nucleotides or bases. SNP represents an alteration in DNA sequence
at a single nucleotide position. Microsatellite markers have higher variability or
heterozygosity compared to the biallelic SNP markers. On the other hand, SNP
markers are more abundant in human genomes, averaging one SNP per 500 to
1000 nucleotides compared to one microsatellite per 30,000 nucleotides. Recently,
techniques have been developed that are extremely powerful for multiplexing
biallelic SNP assays, which offer the possibility of simultaneously testing
thousands of SNP loci in genome.
Linkage analysis involves studying the segregation of disease in large
families with disease phenotype. If genetic markers are identified to cosegregate
with a disease phenotype more often than expected by chance, this suggests that
the defective gene is located close to these markers. Statistical analysis is used to
compare the likelihood that two loci are linked to the phenotype to the likelihood
that two loci are not linked. The common logarithm of ratio of these two likelihoods
is the log-of odds ratio, which is called the LOD score. A maximum LOD
score of 3.0 or greater is used as the criterion that two autosomal loci are linked,
because the odds in favor of linkage with this LOD are 1000 to 1 or greater. A LOD
score of −2.0 or less is considered to be sufficient to exclude linkage between two
loci, because the chance that these loci are linked is only 1 to 100 or less.
One aspect critical to determining the gene involved in a disease is the
identification of families with multiple affected members. We initially identified
families with multiple members with TAAD. The DNA was collected from these
families for genetic studies. In addition, we determined that the disease in these
families was not due to mutations in the FBN1 gene, the defective gene that causes
the MFS.
For our gene mapping studies for familial TAAD, we have primarily used a
large family to map the chromosomal location of the defective gene causing the