The Fulda (Hesse) patient had onset of memory loss at 47 years of age. Her father had onset of dementia at 64 years of age and died at 76 years. The paternal grandmother had onset at 48 years of age and died at 52 years. The American VG families have a mean age at onset of 55.5 years and mean age at death of 64 years. Not only are the onset ages similar between the VG and German families, the surname of the German family also occurs in one of the American VG families.
The genotype data for the 6 PSEN2
tagging SNPs was obtained for the CEPH and VG subjects. A total of 11 forced haplotypes were identified among the CEPH European and VG samples. The GTTACG haplotype (H1) is predominant (42%) among subjects from the VG families; this haplotype is only the fourth most frequent (13%) among the HapMap CEU sample (). All affected persons in the VG families share an identical PSEN2
haplotype based on these SNPs. The same haplotype was also found in the affected individual from the German family (patient III-24
Frequencies of Haplotypes and Alleles of the Markers Segregating With the N141I Mutation
The N141I mutation resides on the H1 haplotype (H1mut) shared by the affected subjects from the VG families; however, a wild-type version of the H1 haplotype (H1wt) is also present in the families in high frequency (). Thus, the H1mut/H1wt diplotype is common among the affected subjects in the VG families. The proband from Fulda also carries this diplotype but, because of the high frequency of the H1 haplotype, this alone is not sufficient to demonstrate shared ancestry of the VG pedigrees and the proband from Fulda. Attempts to identify additional genetic variants within this H1 haplotype group by genomic resequencing were unsuccessful, as no additional polymorphisms were identified.
To demonstrate that the proband from Fulda has the identical PSEN2 mutation haplotype as the VG families, we tested and defined subhaplotypes for the H1 haplotype group by genotyping short tandem repeats markers that flank the PSEN2 gene. Among the VG subjects, single alleles at D1S479 and D1S225 segregate with affectation status. The summarizes the frequencies of these alleles and the H1 SNP haplotype among genotyped VG and CEPH European subjects.
If we assume that the 2 short tandem repeats loci and haplotypes in PSEN2
are in linkage equilibrium, which is reasonable given their physical distance,6
then using the CEPH European allele frequencies, we can estimate the probability that the Fulda proband would share both risk alleles with the VG families as 0.0084. Under the assumption of linkage equilibrium among all 3 loci, the probability of the Fulda proband sharing the 2 risk alleles by chance with the VG families is between 0.1% and 0.2%, depending on whether one uses the CEPH European or the VG N141I noncarrier PSEN2
H1 haplotype frequency for estimation.