Acute Aortic Disease.. - Index of

Genetic Basis of Thoracic Aortic Aneurysms 109
disease in the family. This approach is used in an attempt to avoid problems in
mapping the gene due to genetic heterogeneity; that is, many different genes can
cause disease in unrelated families. To map the first locus for familial TAAD, a
genome-wide scan for the genetic defect causing the aortic disease was done using
DNA from affected members from families TAA002 and TAA003. Genome-wide
scan was performed using ABI Prism Linkage mapping sets-MD-10, which contains
382 microsattelite markers spaced approximately 10 cM apart throughout
the genome. The marker data were analyzed using the affected-pedigree-member
method of linkage analysis because of the decreased penetrance of the disorder.
This analysis revealed three loci with multiple linked markers showing highly statistically
significant regions of linkage for the TAAD gene in these families. Three
candidate loci, a 38 cM region of chromosome 3q, a 52 cM region of chromosome
5q, and a 26 cM of region chromosome 16q, showed multiple linked markers
significantly associated with the disease. Fine mapping was performed to verify
the observed linkage using more microsatellite markers located on three candidate
loci. Fine mapping used DNA from five TAAD families that included 18 affected,
33 unknown, and 14 unaffected individuals. The result of this analysis excluded
the 3q and 16q loci as the location of the defective gene causing TAAD. However,
three of the five families studied showed evidence of linkage to 5q markers.
Further fine mapping was performed on 15 TAAD families using 21 microsatellite
markers to confirm the 5q loci and identify the critical interval. Linkage
analysis confirmed that markers on 5q were linked to TAAD. Pairwise and multipoint
LOD scores were calculated using MLINK and LINKMAP programs of the
computer software FASTLINK version 3.P. Allele frequencies for each marker
were obtained using the founders in the pedigrees. Based on the proportion of
affected individuals in the pedigrees, the penetrance for the homozygous and
heterozygous carriers of the disease allele was deduced as 10% for individuals
under the age of 30 years, 30% between ages 30 and 40, 70% between ages 40
and 60, and 90% for individuals older than 60 years.
Linkage analysis showed that some of the families had significant positive
LOD scores, whereas some of the families had significant negative LOD scores.
Therefore, a heterogeneity test was performed to determine if the families with
positive LOD scores are linked to the marker locus, while the families with negative
LOD scores are unlinked to the marker locus (18). This analysis was done for the
marker D5S2029 since this marker demonstrated the highest LOD score in some
families. This analysis supported genetic heterogeneity for the condition (p = 0.004).
The estimate of alpha, the proportion of families that are linked, was found to be
0.45. Nine families with the highest conditional probability of being linked to
5q13–14 were used for the multipoint analyses. A maximum LOD score (Z max) of
4.74 at no recombination (θ = 0) was obtained for the marker D5S2029. Family
TAA002 has the highest LOD score of 1.75 for this marker (Fig. 5). Pairwise and
multipoint LOD scores were tested in 38 TAAD families and 13 families showed a
positive LOD score at TAAD1 locus with maximum LOD score 6.5 for marker
D5S2029. This result indicates that the TAAD1 locus is a major locus for TAADs.