In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Phenotype predictions for exon deletions/duplications: A user guide for professionals and clinicians using Becker and Duchenne muscular dystrophy as examples
Today’s pick is from the journal Genes by He et al on benign duplications in the DMD gene. Important message for people involved in prenatal screening. 10.3390/genes13111972 For more information see also: https://pubmed.ncbi.nlm.nih.gov/31356707/
Mutations in the dystrophin (DMD) gene underlie both Duchenne & Becker muscular dystrophy. ~8% of mutations are duplications of one or more exons. The dystrophin gene is located on the X-chromosome, so most patients are males, while females are carriers (sometimes with symptoms)
Here authors present with a Chinese female who was pregnant and for whom non-invasive prenatal screening (NIPS) was done. This identified a double duplication of exon 51-53 and exon 64-79. The mothers was a carrier. No family history of Duchenne or Becker or muscle problems.
Parents decided to terminate the pregnancy. Authors did more family analysis and discovered the female’s father ALSO had the double duplication – he had no symptoms whatsoever of Duchenne or Becker and CK was normal. So this duplication was classified as benign by the authors.
They performed long read sequencing and this revealed exon 1-79 of the dystrophin gene was present (enabling dystrophin protein production) and the double duplications of exon 51-53 and 64-79 was OUTSIDE of the gene.
Location matters with duplications! When they are not within the gene, this will not affect dystrophin protein production. Authors suggest performing segregation analysis upon random findings of duplications – if healthy males carry them as well they are benign.
Obviously, when duplications are found in patients with symptoms reminiscent of Duchenne or Becker, the most likely explanation is that the duplication is within the dystrophin gene. However, when prenatal analyses are done you do not know whether the duplication is benign or not
Note that the authors have two types of duplication in one individual. The exon 64-79 duplication would be benign even if it was in the dystrophin gene, since it would be exon 1-79-64-79 –> dystrophin can be produced. Same goes for duplications affecting exon 1.
As long as exon 1-79 are present continuously dystrophin production should not be affected. The exon 51-53 duplication is different. If it is IN the dystrophin gene it would be expected to occur like this: exon 1-53-51-79. THAT is disrupting the genetic code so expect Duchenne
However, if the extra exon 51-53 is outside of the dystrophin gene, exon 1-79 are present normally and there is no Duchenne expected. So it is not the duplication that matters here but its location.
The problem is that some people do not realize all this and will report anything affecting the dystrophin gene as Duchenne. When these mutations end up in mutation databases as pathogenic, others will assume due diligence was done and copy this misinterpretation.
Also people may not understand the difference between a duplication within or outside of the dystrophin gene. What this underlines is that the dystrophin gene is complex, and that experts should be consulted to help with interpretations.