THE AGE OF HUMAN MUTATION - GENEALOGICAL AND LINKAGE DISEQUILIBRIUM ANALYSIS OF THE CLN5 MUTATION IN THE FINNISH POPULATION

Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an a utosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1/1,500. We re cently assigned the locus for vLINCL, CLN5, to 13q21.1-q32. In the pre sent study, the haplotype analysis of Finnish CLN5 chromosomes provide s evidence that one single mutation causes vLINCL in the Finnish popul ation. Eight microsatellite markers closely linked to the CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared haplotype analysis. One single haplotype formed by flanking markers D1 3S160 and D13S162 in strong linkage disequilibrium (P <.0001) was pres ent in 81% of disease-bearing chromosomes. Allele 4 at the marker locu s D13S162 was detected in 94% of disease-bearing chromosomes. To evalu ate the age of the CLN5 mutation by virtue of its restricted geographi cal distribution, church records were used to identify the common ance stors for 18 vLINCL families diagnosed in Finland. The pedigrees of th e VLINCL ancestors merged on many occasions, which also supports a sin gle founder mutation that obviously happened 20-30 generations ago (i. e., similar to 500 years ago) in this isolated population. Linkage dis equilibrium was detected with seven markers covering an extended genet ic distance of 11 cM, which further supports the young age of the CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 gene was predicted to lie similar to 200-400 kb (total range 30-1,360 kb) from the closest marker D13S162.