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#apaperaday: Genetic counseling for the dystrophinopathies—Practice resource of the National Society of Genetic Counselors

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Genetic counseling for the dystrophinopathies—Practice resource of the National Society of Genetic Counselors

Today’s pick is from journal of genetic counseling by Pickart et al with a practice resource for dystrophinopathy counseling to commemorate my genetics talk later today at TREAT-NMD masterclass. DOI: 10.1002/jgc4.1892

This is a very nice reference document that includes a lot of information I’m teaching today at the Duchenne masterclass. The resource was generated by USA counselors with dystrophinopathy expertise and based also on literature available in English.

Dystrophin protects muscle fibers from damage during contraction by providing a link between actin and connective tissue. The dystrophin gene is located on the X chromosome which means that men with a mutation will have no backup copy while women will have a backup.

Dystrophinopathies used to be defined as Duchenne and Becker, where Duchenne patients cannot produce functional dystrophin with a severe disease progression and Becker patients produce partially functional dystrophins and a milder disease progression.

However with improved care the definitions become blurry and dystrophinopathy is used more and more. The resource contains information on symptoms and natural history and treatment options. I will focus the thread on genetic and counseling specific aspects.

Duchenne is diagnosed at 4.1 years on average in the USA and Becker at 14.5. Authors stress that Becker has more variability in symptoms onset age and progression rate. As dystrophin is also expressed in the brain, learning difficulties are seen for both Duchenne and Becker.

While women have a “backup copy” many carriers do have some symptoms and all are at risk for developing cardiomyopathy. Female dystrophinopathy can vary from weakness and pain to pathology resembling Becker or Duchenne.

Female carrying a mutation on one dystrophin gene have a 50% chance of giving the X chromosome with this mutation to a son (Duchenne or Becker) or a daughter (carrier). A male with dystrophinopathy will have a 100% chance of giving the mutation to his daughters.

Authors stress a high de novo rate, i.e., women who are not carriers can have sons with Duchenne or Becker. The mutation is present in a subset of the oocytes for these women, so there is a risk for recurrence even though the mother is not a somatic carrier of the mutation.

Both for carriers and non-carrier mothers of Duchenne or Becker children, genetic counseling to discuss possibilities for future pregnancies have to be discussed. When the carrier status is unknown, the genetic analysis should be done.

Authors discuss that in the past for females at risk, this analysis was often done at adulthood or when women considered parenthood. However, authors argue that many pregnancies are not planned and it may be better to know earlier whether someone is a carrier.

Also because women who carry a mutation are at risk for cardiomyopathy and should be checked regularly for this starting in adulthood. Genetic testing generally does not need a muscle biopsy but only DNA.

In the USA, a one-step approach with next-generation sequencing is used, while in other regions, a two-step approach is still used, looking first for deletions and duplications of one or more exons (75%) and then small mutations if needed (25%).

Authors outline interpretation can be challenging as some variants have never been reported, while others have but with poor quality. There are variants that can lead to both Duchenne and Becker, which makes counseling challenging when a variant is found before onset of symptoms.

Or when carrier screening is done before pregnancy. Here duplications are also notoriously challenging as the duplicated exons may be within the dystrophin gene (pathogenic) or not (not pathogenic).

Authors outline that with various (mutation-specific) treatments now approved it is crucial to find the mutation because there will be treatments available.

Finally, authors outline the diagnosis of Duchenne is overwhelming for the family and patient and psychological support is needed lifelong for both. Especially mothers may feel guilt as “their” gene caused the disease.

The need for psychological support was mentioned today also by the patient representative who kicked off the TREAT-NMD Duchenne masterclass – coping with the diagnosis, but also how to communicate with the son about Duchenne. I commend the authors for this great resource.