The research group of Wouter the Laat from the Hubrecht Institute, together with the Department of Genetics from the UMC Utrecht and several physicians from Greece and Iran have developed a new blood test to detect severe disorders early during pregnancy. This test focusses on monogenic disorders: diseases caused by a single gene, which makes the method much more sophisticated than the NIPT. The new test, abbreviated to MG-NIPD (monogenic non-invasive prenatal diagnosis), may eventually replace invasive prenatal diagnosis methods such as amniocentesis and chorionic villus sampling. The results are published in the American Journal of Human Genetics on August 24.

Severe genetic disorders
Prenatal diagnosis is used to detect severe genetic disorders in the foetus during pregnancy. Two well-known prenatal diagnosis methods are amniocentesis and chorionic villus sampling. These tests, however, can be stressful for mother and child. Therefore, non-invasive prenatal genetic tests have been developed over the past few years that only require a blood sample. Non-invasive prenatal testing (NIPT), for example, has already facilitated the analysis of cell-free DNA in maternal blood to test if the foetus has an extra chromosome, and therefore has Down syndrome, for instance. However, many severe genetic disorders cannot be shown by means of NIPT.

Highly sophisticated method
If parents are carriers of a severe genetic disease, the cause is usually a small genetic variation. Often, only one or a small number of DNA building blocks in one gene have been altered. Examples of such disorders include cystic fibrosis (CF), thalassemia and sickle cell disease (inherited blood disorders). Detection of these monogenetic disorders cannot be done using NIPT, but is possible with MG-NIPD. The new test uses the cell-free DNA in maternal blood. During pregnancy, cell-free DNA consists largely of the mother’s DNA with a hint of foetal DNA. As our DNA consists of more than three billion building blocks, it is extremely complicated to determine accurately whether the foetus has inherited the disorder from both parents. MG-NIPD makes this detection possible. It is a highly sophisticated test that focusses on a single gene and has been developed by the Hubrecht Institute and UMC Utrecht.

TLA technology
The test applies Targeted Locus Amplification (TLA) technology. This is a new method to analyse DNA, recently developed by the Hubrecht Institute and its spin-off company Cergentis. A large advantage of this technology is that it provides separate mapping of the two copies of each gene that every human being has. This is important because the two copies differ from each other in every person. In future parents who carry the disease, one of the two copies contains the disease causing variation. By using TLA technology to determine which DNA variations are unique for the healthy and the pathogenic copy, it is possible to establish hundreds of disease-discriminating variations for both parents. Later, each of the variations can be measured separately in the maternal blood. This enables reliable non-invasive prenatal diagnosis for diseases including cystic fibrosis, thalassemia and sickle cell disease.

At-risk families
This research was supported by the Utrecht University Fund and the K.F. Hein Fund. Patient associations such as the Netherlands Cystic Fibrosis Foundation and Oscar Netherlands (for thalassemia and sickle cell disease carriers and patients) endorse the importance of non-invasive diagnostic tests. The next step is to validate MG-NIPD in large groups of at-risk families in the patient populations of several university medical centers in the Netherlands. These studies will confirm whether MG-NIPD can indeed replace amniocentesis and chorionic villus sampling in the near future. If the results are positive, expectations are that MG-NIPD can be used for prenatal diagnosis in families with monogenic disorders within a few years.

Prof. dr. Wouter de Laat is group leader at the Hubrecht Institute (KNAW) in Utrecht and professor of Biomedical Genomics at the Universitair Medisch Centrum Utrecht en de Universiteit Utrecht.

Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping
American Journal of Human Genetics 2017