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#apaperaday: Further evidence for an attenuated phenotype of in-frame DMD deletions affecting the central rod domain of dystrophin around exon 48

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Further evidence for an attenuated phenotype of in-frame DMD deletions affecting the central rod domain of dystrophin around exon 48

Today’s pick is from American Journal of Medical Genetics by Burger et al on a 3 generation family with a deletion of exon 48 in the dystrophin gene & no phenotype  (or rather: the phenotype was no symptoms) DOI: 10.1002/ajmg.a.63842.

Mutations in the dystrophin gene can cause Duchenne, when no functional dystrophin can be made or Becker when partially functional dystrophins can be made. The dystrophin gene is located on the X-chromosome, so mostly boys/men are affected, but females can also have symptoms.

Duchenne, Becker and female dystrophinopathy patients all also are at risk for developing cardiomyopathy (almost all Duchenne, most Becker and many female dystrophinopathy and even some females who do not have muscle symptoms still will have cardiomyopathy).

Cognitive problems have been reported as well in a subset of patients. Authors here present an in-frame deletion of exon 48, which was found in a 3 generation family. The case started with a pregnant female who had a nephew with dystrophinopathy.

He was accidentally diagnosed after elevated CK plasma levels were found during a blood analysis related to a viral infection (CK is creatine kinase, a muscle damage marker as this enzyme is abundant in muscle and leaks into blood upon muscle damage).

The boy was found to have a deletion of exon 48, but he had no clinical symptoms then or now (2 years later). The mother of the boy was a carrier and her sister (pregnant) turned out to also be a carrier.

She did not opt for analysis of the fetus given the lack of symptoms in her nephew. However, analysis of the father of both sisters revealed he also had the deletion, without any symptoms and normal CK, further confirming that this deletion presents very mild in this family.

Authors discuss that other very mild exon 48 deletion cases have been reported before, but also some cases where patients had more symptoms. Also for other mutations, very mild symptoms were reported and there was often variability in levels of mildness.

Authors discuss that for some of these in-frame deletions, there are also reports of more severe pathology – however, that was from a time when diagnosis was often made with multiplex PCR, which can be inaccurate as it does not include all exons.

Since the introduction of MLPA analysis, which includes all exons, these unexplainable discrepancies have become a lot reduced. I appreciate the authors reported this case – as they correctly point out that databases are enriched for symptomatic cases.

With more genome-wide genetic analyses happening now, it is likely that deletions not giving (much) symptoms will be found more frequently (if there are no symptoms you will not look for mutations of course…so you can only stumble upon them by accident).