Abstract
BackgroundHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder caused by mutations in ENG,ACVRL1, or SMAD4. Around 90% of HHT patients present with a heterozygous pathogenic genetic variation. Almost all cases of HHT have a family history. Very few cases are de novo or mosaicism. We describe a case with mutational mosaicism that would not be observed in the clinical routine when using Sanger sequencing or a NGS read coverage below app. 100.Methods DNA was extracted from peripheral blood leukocytes, and buccal swabs. The coding region, exon–intron boundaries, and the flanking sequences of the genes were sequenced by NGS.ResultsThe proband had clinical HHT fulfilling the Curaçao criteria and genetic testing identified a frameshift mutation in ENG. The mother of the proband, also with clinical HHT, was found negative when analyzing DNA from blood for the familial mutation using Sanger sequencing. Analyzing her DNA by NGS HHT panel sequencing when extracted from both peripheral blood leukocytes, and cheek swabs, identified the familial ENG mutation at low levels.ConclusionWe provide evidence of ENG mutational mosaicism in an individual presenting with clinical HHT. These findings illustrate the importance of considering mutational mosaicism.
Highlights
Hereditary hemorrhagic telangiectasia (HHT), known as Osler–Weber–Rendu disease, is an autosomal dominant hereditary disorder characterized by a variety of clinical manifestations due to the presence of multiple mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs, most commonly lungs, liver, and cerebrum
We provide evidence of ENG mutational mosaicism in an individual presenting with clinical HHT
We here present NGS sequencing data showing mosaicism for a pathogenic genetic variation in an individual presenting with symptoms of HHT
Summary
Hereditary hemorrhagic telangiectasia (HHT), known as Osler–Weber–Rendu disease, is an autosomal dominant hereditary disorder characterized by a variety of clinical manifestations due to the presence of multiple mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs, most commonly lungs, liver, and cerebrum. HHT is a genetically heterogeneous disorder caused by mutations in three known genes: ENG (OMIM 131195), ACVRL1 (OMIM 601284), and SMAD4 (OMIM 600993). In NGS analysis of these genes, usually patients present with a pathogenic genetic variant in a heterozygous state with an equal representation of the two alleles. Mutational mosaicism in HHT has been described it is very rare. Mutational mosaicism confirmed by NGS, which is much more precise, has, to our knowledge, only in very few cases been described in the HHT genes. We show the presence of an ENG mutational mosaicism that would not be observed in the clinical routine if using Sanger sequencing or a NGS read coverage below app. We show the presence of an ENG mutational mosaicism that would not be observed in the clinical routine if using Sanger sequencing or a NGS read coverage below app. 100
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