Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 .. severe fatigue, 2023, Oakley et

Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue


Abstract
Background
Causative genetic variants cannot yet be found for many disorders with a clear heritable component, including chronic fatigue disorders like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These conditions may involve genes in dicult-to-align genomic regions that are refractory to short read approaches. Structural variants in these regions can be particularly hard to detect or dene with short reads, yet may account for a signicant number of cases. Long read sequencing can overcome these difficulties but so far little data is available regarding the specic analytical challenges inherent in such regions, which need to be taken into account to ensure that variants are correctly identied. Research into chronic fatigue disorders faces the additional challenge that the heterogeneous patient population likely encompasses multiple aetiologies with overlapping symptoms, rather than a single disease entity, such that each individual abnormality may lack statistical signicance within a larger sample. Better delineation of patient subgroups is needed to target research and treatment.

Methods
We use nanopore sequencing in a case of unexplained severe fatigue to identify and fully characterise a large inversion in a highly homologous region spanning the AKR1C gene locus, which was indicated but could not be resolved by short-read sequencing. We then use GC-MS/MS serum steroid analysis to investigate the functional consequences.

Results
Several commonly used bioinformatics tools are confounded by the homology but a combined approach including visual inspection allows the variant to be accurately resolved. The DNA inversion appears to increase the expression of AKR1C2 while limiting AKR1C1 activity, resulting in a relative increase of inhibitory neurosteroids and impaired progesterone metabolism.

Conclusions
This study provides an example of how long read sequencing can improve diagnostic yield in research and clinical care, and highlights some of the analytical challenges presented by regions containing tandem arrays of genes. It also proposes a novel gene associated with a specic disease aetiology that may be an underlying cause of complex chronic fatigue and possibly other conditions too. It reveals biomarkers that could be assessed in a larger cohort, potentially identifying a subset of patients who might respond to treatments suggested by the aetiology.

Link to free full text https://assets.researchsquare.com/f...-e3fe-41f8-a5f0-88fa9c1b5543.pdf?c=1695308213

The discussion and results are interesting.

 

Link to online version, https://www.researchsquare.com/article/rs-3218228/v2

 

For me the take home message is

a) this seems to be more evidence that hormone dysfunction is a possible path to ME/CFS.
b) structural genomic variants are hard to detect with the usual methods, and can sometimes explain an illness.
c) this is also more evidence that in-depth genetic testing of people with ME/CFS and a family history of fatigue and/or ME/CFS could be a useful research project. The abnormalities are there, we just need to find them.

 

Perhaps I'm misreading this, or it can be chalked up to awkward wording, but I am unaware that anyone has irrefutably demonstrated yet that ME/CFS has a clear heritable component.

 

I have no idea what any of those devices are. We're living in the future.

They make no mention of PEM, but that her diagnosis of ME/CFS was eventually removed. Maybe she didn't have PEM? It's an interesting paper nonetheless.

 

Looks like it was based on data from only 1 patient?

 

Now published, https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04711-5

 

Another important message from this paper is that we may have been missing highly significant genetic abnormalities in ME/CFS because of technical limitations.

Many families have an at least partially inherited form of ME/CFS but despite this we know very little about the genetic basis of the illness. Maybe the genetic causes in these cases are in regions of the genome that are difficult to work with.

 

Just wondering if looking for rare cases like this* could be a way to identify the disease mechanism for large(r) groups of people with ME/CFS?
*"increase the expression of AKR1C2 while limiting AKR1C1 activity, resulting in a relative increase of inhibitory neurosteroids and impaired progesterone metabolism."