TLA Technology: a new DNA diagnostic test to sequence genes that cause the disease and detect new mutations: proof of concept study voor patients with Rendu-Osler-Weber disease.

DNA Diagnostics is important in prenatal and postnatal diagnostics. Currently
there is already genetic tests for ~1300 genes in the Netherlands.
*Personalized medicine*, where each patient receives tailor-made treatment
based on his/her own genetic profile, is increasingly applied in the treatment
of various cancers. A well-known example is breast cancer. Depending whether a
patient scores positive for the human EGF receptor 2 (HER2+), the estrogen
receptor (ER+) or the progesterone receptor (PR+), he/she receives the
corresponding, dedicated, hormone treatment. With the uncovering of the human
genome sequence and the rapid progress in the discovery of genes causing
disease, the relevance of DNA diagnostics for human healthcare will only
increase. The number of drugs with a so-called pharmacogenomics label, where
prescription depends on the outcome of a genetic test, is expected to
substantially increase in the future. Current DNA analysis strategies often
still rely on PCR amplification of the coding parts (exons) of the genes of
interest. For example, the analysis of the hereditary breast cancer genes
BRCA1&2 genes, involves almost 200 independent PCR reactions that each are then
analyzed by Sanger sequencing. It enables the detection of single nucleotide
changes and small insertions/deletions (indels) in the coding parts of these
genes. Additional tests, such as Multiplex ligation-dependent probe
amplification (MLPA), are required to detect the possible loss of alleles. The
combination of these approaches is expensive, it often takes weeks or even
months to get the results, and most importantly, the analyses are incomplete.
Structural variation in the genome, such as translocations, inversions and
insertions (Figure 1) are not detected by any of the current strategies used in
clinical DNA diagnostics. However, they account for an estimated 5-20% of all
genetic variation present in the genome. This implies that currently a
substantial percentage of patients erroneously scores negative for mutations in
clinically relevant genes. To circumvent this in the future, there is a need
for cheap and fast technologies that provide the complete sequence of genes of
interest.

1. Validation - of an independent geneset - of TLA technology as a new DNA
diagnostic test for complete sequencing of selected genes.
2. The search for structural chromosome changes in patients with ROW disease
who where tested negative for mutations in an earlier test.

This study is partly blinded. The investigator of St Antonius hospital is known
with the mutations within the stuydpopulation but the investigator in the
Hubrecht Institute is blinded.

The test will have minor burden for Patients. Patients will have a regular
bloodtest with - for the study - two extra bloodsamples (two tubes) that will
be collected. There are no risks for the patients who participate.