Tissue‐specific mosaicism in hereditary hemorrhagic telangiectasia: Implications for genetic testing in families

: Mosaicism in hemorrhagic telangiectasia (HHT) has been previously identified when testing blood samples of HHT patients. We report the first detection of mosaicism not involving blood of a family proband, and discuss implications for genetic testing algorithms in HHT families. Sanger sequencing and large deletion/duplication analysis in a patient with HHT identified no pathogenic variant in ENG, ACVRL1, or SMAD4. Exome sequencing was then performed on this proband, as well as her affected adult child. A pathogenic ENG variant was detected in the proband's affected child, but not in DNA extracted from peripheral blood of the affected parent/proband. Additional tissue samples (saliva and hair bulbs) were obtained from the proband. The variant was not detected in saliva, but was detected in the hair bulb sample (at 33%). This is the first report of an HHT patient with mosaicism in whom the disease-causing mutation was not detected in blood. The molecular findings in this family suggest that the possibility of mosaicism not present or detectable in blood should be considered if a proband with HHT tests "negative" for a mutation in known genes. This occurrence is particularly suspect for families in which the proband does not have a clearly affected parent. This mechanism may explain some patients with classic HHT in whom a pathogenic variant has not been identified in one of the known HHT genes.