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#apaperaday: Accuracy of Non-Invasive Prenatal Testing for Duchenne Muscular Dystrophy in Families at Risk: A Systematic Review

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Accuracy of Non-Invasive Prenatal Testing for Duchenne Muscular Dystrophy in Families at Risk: A Systematic Review

Today a systematic review paper from the journal Diagnostics on non invasive prenatal testing for Duchenne in families at risk (due to a family history) by Zaninovic et al DOI: 10.3390/diagnostics13020183

Non-invasive prenatal screening test (NIPT) makes use of the fact that during pregnancy DNA from the fetus is present in the blood of the mother. This allows testing for genetic diseases when it is known that a family is at risk by comparing dosages of chromosomes.

For Duchenne 2 types of analysis have been used:

  1. The haplotype method – this means that you check which chromosome (or region of the chromosome around the affected gene) is inherited by the fetus: the one with the mutation or the normal one.
  2. The mutation based method. This involves specific probes tailored to the mutation. Both methods work with ratios, because of course the DNA of the mother is present in high abundance in the blood of the mother. Fetal DNA is low abundant.

Chromosomes and/or chromosome regions can be discriminated because there are common variants (single nucleotide polymorphisms). So you can see which combination of variants is present in the chromosomes of the father and the mother and then compare that to the fetus.

The challenge with Duchenne is that it is X-linked. Females have 2 X chromosomes, males only 1. So if the fetus is a boy, the relative amount of X-chromosome DNA is lower than for the other chromosomes (where both males and females have 2 copies).

Authors found 7 studies where NIPT was used in families at risk: someone in the family had Duchenne or a noncarrier mother had son with Duchenne. Note that even if women are not a carrier, there is a risk of a second child with Duchenne as part of her eggs will have the mutation.

The mutation specific approach is very accurate but it requires that the mutation is identified. For the haplotype specific approach this is not required, but you do need to know which X-chromosome has the mutation – so you need DNA from an affected family member.

If you have DNA from the father as well that makes things easier and more accurate. A challenge with the haplotype approach is that the DMD gene is very big and recombination can occur (in the eggs of the mother the X-chromosomes exchange material).

This means you THINK you are looking at X chromosome A (healthy), but part of this X chromosome was exchanged with X chromosome B. If the exchange involved part of the DMD gene (i.e. ~10% of the X chromosome because it is so huge), the mutation may now be on the other chromosome.

Authors discuss that the challenge of NIPT for Duchenne is that the disease is quite rare and that there are no guidelines for quality controls. They outline that in some cases the amount of fetal DNA was too low and new blood samples had to be obtained, causing delays.

However, NIPT can be done starting at 7 weeks post gestation, which is earlier than the amnion and chorion tests that also include a risk of miscarriage or stillbirth. Authors stress that NIPT should only be offered in combination with genetic counseling.

The NIPT may reveal that the child has Duchenne, which involves a very difficult and personal decision for the family. Good guidance is crucial here. An interesting read, but it involves complex genetics, so suggested only for those who appreciated that.