A PEDIGREE ANALYSIS WITH MINIMIZED ASCERTAINMENT BIAS SHOWS ANTICIPATION IN MET30-TRANSTHYRETIN RELATED FAMILIAL AMYLOID POLYNEUROPATHY

In type I familial amyloid polyneuropathy (FAP) caused by a variant Me t30-transthyretin (TTR), genetic anticipation has been reported. To de termine whether anticipation of the disease is a true biological pheno menon or the result of ascertainment bias, we compared age at onset of the affected child with that of the affected parent in 68 parent-chil d pairs (including data on assumed age at onset and on asymptomatic ob ligate heterozygotes and parents at obligate 50% risk) in 15 families. Excluding the parent-child pairs involving the proband and ''bilineal pairs'', onset occurred earlier in the child than in the transmitting parent in 60 out of 68 ''unilineal pairs''. After correction for asce rtainment bias resulting from incomplete penetrance and reduced biolog ical fitness in early onset patients, the number of anticipation pairs (60 pairs) was still significantly larger than that of non-anticipati on pairs (29.7 pairs) (p<0.05). When the children were sons, the diffe rence in age at onset was significantly greater in the mother-son pair s than in the father-son pairs (p=0.023). Although not all ascertainme nt biases could be eliminated, these data show strong evidence that an ticipation in the transmission of Met30-TTR FAP is a true biological p henomenon.