Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.

Mutations in the ENG gene on chromosome 9 (HHT 1) and in the ALK-1 gene on chromosome 12 (HHT 2) have been reported as causes of hereditary hemorrhagic telangiectasia (HHT). HHT 1 has been correlated with a higher prevalence of pulmonary arteriovenous malformations than HHT 2. Other distinct phenotype-genotype correlations have not been described. The prevalence of HHT in the county of Fyn, Denmark, was 15.6 per 100,000 on January 1, 1995. All living patients and their first-degree relatives were invited to attend a detailed clinical examination and blood was drawn for mutation analysis. In two families mutations were identified in exon 8 of the ALK-1 gene. In family 6 we found a T1193A mutation. In this family a high prevalence of PAVM and severe GI bleeding was documented, while in family 8 with a C1120T mutation no individuals with PAVM were identified and only one patient had a history of severe GI bleeding. No mutations in the endoglin locus were found in either family.