A couple of months ago we received an email from Danny Miller, founder of the MEPAN Foundation. He wrote with what, on the surface, would seem to be a simple request: would we consider adding the MECR gene to our movement disorder, mitochondrial and neurology in-silico panels?
Not being specifically familiar with MEPAN, we looked into the published studies. We learned that MEPAN stands for Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration. It is also referred to in different sources as MECR-Related Neurologic Disorder as well as Dystonia, Childhood-Onset, with Optic Atrophy and Basal Ganglia Abnormalities (DYTOABG).
The disorder is characterized by a combination of childhood-onset dystonia, distinctive basal ganglia degeneration visualized by MRI and optic atrophy which usually has a slightly later onset. The dystonia may be accompanied by chorea and/or ataxia and dysarthria may lead to impaired speech. The clinical presentation is quite similar to that of mitochondrial disorders, with MEPAN differing most significantly by the relative absence of cognitive regression that is almost always seen with mitochondrial disease. This similarity, as well as similarity to other movement disorders, suggests that MEPAN may be underdiagnosed.
As of February 2020, only 17 individuals with MEPAN have been identified world-wide. All harbor recessive variants in the MECR gene which encodes mitochondrial trans-2-enoyl-coenzyme A-reductase, an enzyme involved in the mitochondrial fatty acid synthesis (mtFAS) pathway important for protein lipoylation and respiration.
The only way to confirm a suspected MEPAN diagnosis is through genetic testing. But as MEPAN is a relatively newly characterized disorder, MECR is not included in most panel tests. Which is what led Danny to reach out to us.
Expanding testing of MECR through in-silico panel expansion
For many genetic test providers, adding a gene to a panel is not an easy undertaking. If the gene wasn’t selected a priori at the time the panel was established, the underlying assay will be missing the necessary primers for amplification. Extending the wet bench assay to amplify the region with appropriate coverage is not a small undertaking.
Fortunately, performing a panel test using in-silico analysis on a whole genome sequencing (WGS) backbone makes adding a gene much simpler. (See our previous post for a deeper discussion of why we’ve chosen the approach of combining WGS with in-silico analysis).
Once we were able to establish the gene’s clinical relevance, it was straightforward to check coverage of MECR on a nucleotide-by-nucleotide level across a series of validation samples. When all validation samples passed with appropriate coverage, the gene was formally introduced into the three previously mentioned in-silico panels. A process that could have taken months to years of effort with a different technology was resolved in about a week.
Enabling evaluation of MECR variants within our relevant tests through in-silico panel expansion is a very small contribution to the effort to raise awareness about MEPAN and its potential underdiagnosis and, through greater awareness, to drive research into potential treatments. But it’s one that we are proud to have been able to make.
For more information about MEPAN, please reach out to the MEPAN Foundation.
Heimer et al. MECR-Related Neurologic Disorder. GeneReviews. May 9, 2019. PMID 31070877
Heimer et al. MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. Am J Hum Genet. 2016 Dec 1; 99(6): 1229–1244. PMID 27817865