Background Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder affecting the vascular system, characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. Mutations in two genes, ENG and ACVRL1, account for the majority of cases. Almost all cases of HHT show a family history of HHT-associated symptoms; few cases are de novo. Mutational mosaicism is the presence of two populations of cells, with both mutant and normal genotypes in one individual and generally occurs through de novo mutation events in embryogenesis. Some isolated cases of HHT with no detectable ENG or ACVRL1 mutation may be caused by a mosaic ENG or ACVRL1 mutation that is present at levels below the limit of detection of current molecular screening methods.

Objective To identify clinically relevant mosaicism in type I HHT.

Methods Sequencing, quantitative multiplex-PCR and marker analysis were used to identify three HHT families with founders who showed mosaicism for endoglin mutations. Where available, mosaicism was verified by testing different sampling sites, including blood, hair and buccal swabs.

Results All three mosaic samples exhibited the mutation in an estimated ≤25% of the DNA. Two of the mosaic patients had clinically confirmed HHT by the Curaçao criteria and the other showed symptoms of HHT. In each case the heterozygous mutation had already been identified in another family member before detection in the mosaic founder.

Conclusions The results show the importance of investigating patients without prior family history for the presence of mutational mosaicism, as detecting this would enable appropriate genetic screening and targeted medical care for at-risk children of mosaic patients.