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#apaperaday: Identification of Biallelic dystrophin gene variants during maternal carrier testing for Becker muscular dystrophy and review of the DMD exon 49–51 deletion phenotype

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Identification of Biallelic dystrophin gene variants during maternal carrier testing for Becker muscular dystrophy and review of the DMD exon 49–51 deletion phenotype

The paper is from Ulm et al published in Molecular Genetics & Genomics Medicine about a woman with 2 different in-frame deletions in the dystrophin gene with mild dystrophinopathy symptoms. DOI: 10.1002/mgg3.2088

Pathogenic variants in the dystrophin gene can lead to Duchenne (disrupting the genetic code/out-of-frame variants), Becker (maintaining the genetic code/in-frame variants) or X-linked cardiomyopathy (in-frame variants only leading to heart pathology).

As the dystrophin gene is located on the X-chromosome, these diseases occur primarily in men, who have only a single X-chromosome so when there is a pathogenic variant, there is no ‘back-up’. Women who carry pathogenic variants have a back-up chromosome, but can have symptoms.

Symptoms can vary from mild cramps & weakness to more debilitating, progressive weakness. Here authors present a 28 year old woman with 3 sons, 2 diagnosed with Becker (deletion exon 45-47). The mother turned out to have this deletion, but also a deletion of exon 49-51.

Authors then investigated the 3rd son, who carried the deletion of exon 49-51. This confirms the deletions are present on 2 different X-chromosomes in the mother. She had muscle cramps but no weakness or heart problems. The son with deletion 49-51 was asymptomatic (CK normal).

A note (not discussed by the authors): the son has no symptoms YET – he may still develop them at an older age. The mother may as well. Skeletal and heart. So this should be monitored. Authors performed literature reviews to assess deletion exon 49-51 patients.

They found 27 cases, some with Becker, some with cardiomyopathy but also some with Duchenne. They also looked into their own database, finding 15 cases with the exon 49-51 deletion. These were all mild cases, including some asymptomatic individuals.

3 of the asymptomatic cases had an autism spectrum diagnosis and were sequenced due to developmental delay. Authors discuss that autism is more frequent in dystrophinopathies. I will add that speech delay is common too, and sometimes picked up before skeletal muscle symptoms.

Authors discuss that in literature some cases with an in-frame exon 49-51 deletion were reported to have Duchenne. These were primarily older reports. Authors discuss the patients can be misdiagnosed – either the deletion (e.g. exon 49-52 is out of frame) or the Duchenne aspect.

Both are possible. Before MLPA, deletions were not always accurately picked up. Secondly, some clinicians with less experience with the complexities of the dystrophin gene will label all pathogenic variants as Duchenne (DMD gene mutation –> Duchenne), not considering Becker.

This still happens in the current day – especially now that whole exome sequencing is done centrally and non-specialist misinterpret the variants or are not aware of the fact that variants can cause Duchenne or Becker. Obviously this is something with massive impact for families.

Back to the paper: authors also did a literature review of women with pathogenic variants on each X-chromosome. So far 6 other cases were reported, one of which an asymptomatic individual with a deletion of exon 16-29 (in-frame) and a duplication of exon 1-34 (not pathogenic!)

Authors do not discuss this case, but a duplication of exon 1-34 can mean

  1. It is in the dystrophin gene meaning the individual has exon 1-34 and then exon 1-79 –> dystrophin can be produced.
  2. The deletion is outside of the dystrophin gene –> dystrophin can be produced.

So it is not surprising this woman is asymptomatic. Going to plug the educational paper I wrote about this with Prof. Den Dunnen, as also here mislabeling can have dire consequences.

I like the publication and I commend the authors for taking the time to dive into the literature to provide context. Some aspects could have been elaborated on more (see thread) but all in all it is an interesting paper.