GENETIC BACKGROUND OF CONGENITAL CHLORIDE DIARRHEA IN HIGH-INCIDENCE POPULATIONS - FINLAND, POLAND, AND SAUDI-ARABIA AND KUWAIT

Congenital chloride diarrhea (CLD) is an inherited intestinal disorder caused by mutations in the down-regulated in adenoma gene. In Finland , the disease is prevalent because of a founder effect, and all but on e of the CLD-associated chromosomes carry the same mutation, V317del. In Poland, another area with a high incidence of CLD, as many as seven different mutations have been detected so far. A third known cluster of CLD, around the Persian Gulf, has not been genetically studied. We studied the allelic diversity of CLD in Poland, in Saudi Arabia and Ku wait, and in three isolated families from North America and Hong Kong. Altogether, eight novel mutations were identified, making a total of 19 known CLD gene mutations. The Polish major mutation I675-676ins was found in 47% of the Polish CLD-associated chromosomes. Haplotype anal ysis and clustering of the I675-676ins mutation supported a founder ef fect and common ancestral origin. As in Finland, a major founder effec t was observed in Arab patients: 94% of the CLD-associated chromosomes carried a nonsense mutation, G187X, which occurred in either a conser ved ancestral haplotype or its derivative, Our data confirm that the s ame locus is mutated in all cases of CLD studied so far. In Poland, a relatively common founder mutation is likely to highlight a set of rar e mutations that would very rarely produce homozygosity alone. This su ggests that mutations in the CLD locus are not rare events. Although t he disease is thought to be rare, undiagnosed patients may not be unco mmon.