Two common endoglin mutations in families with hereditary hemorrhagic telangiectasia in the Netherlands Antilles: evidence for a founder effect

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleedi ng disorder characterized by localized angiodysplasia. Mutations in either of two genes, endoglin or ALK-1, can cause HHT. Both genes encode putative receptors for the transforming growth factor-beta superfamily of ligands. M any mutations in each gene have been identified in HHT kindreds from around the world, and with few exceptions mutations an unique and family specific . The prevalence of HHT in the Leeward Islands of the Netherlands Antilles is possibly the highest of any geographical location. We wished to establis h whether this high prevalence is due to a genetic founder effect or to mul tiple mutational events. HHT kindreds from the Netherlands Antilles and The Netherlands were screened for mutations in the two genes associated with H HT. Haplotype analysis of a 5-cM region on chromosome 9 flanking the endogl in gene revealed three distinct disease haplotypes in the ten Antillean fam ilies stud led. Seven of these families share a splice-site mutation in exo n 1 of endoglin. Two other Antillean families share a missense mutation in exon 9a of endoglin. This mutation was also found in a Dutch family that sh ares the same disease haplotype as the Antillean families with this mutatio n. Thus it appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colon ist. The limited scope of mutations suggests that a presymptomatic screenin g program for HHT would be feasible in this population.