- ENG (endoglin). Hereditary hemorrhagic telangiectasia type 1 (HHT1).
- ACVRL1 (ALK1). Hereditary hemorrhagic telangiectasia type 2 (HHT2).
- SMAD4 (MADH4). Some patients with JP-HHT may show only symptoms of HHT with occult manifestation of juvenile polyposis (JP). The mutations leading to JP-HHT are most often found in the COOH-terminus of SMAD4.
Copy number changes
Our lab uses quantitative multiplex PCR to look for whole-exon and multi-exon deletions and duplications; this method simultaneously screens for small intra-exon insertions and deletions.
Our sequence analysis is highly sensitive and is able to detect mosaic mutations at the level of 15% or greater. We consider reported polymorphisms when designing our sequencing assays to ensure the accuracy of our sequence results.
Splice site analysis
We sequence a minimum of 25 nucleotides flanking each exon to detect changes in splice sites. We use in silico analysis and scoring to determine whether a particular change is likely to cause missplicing. In the case of an intronic variant of uncertain significance we perform RNA transcript analysis on a fresh blood sample at no added charge.
Amino acid conservation analysis
For missense amino acid changes of uncertain significance we employ several in silico conservation analysis programs to predict whether a particular missense change is likely to be pathogenic. In addition, when appropriate we will test known affected and unaffected relatives at no charge to clarify variant classification.