Diagnostic Gap

There have been a number of papers in recent times which talk about a diagnostic gap in HSP. I wanted to explore what this means.

Many of you will know that the first identification of a gene for HSP happened in 1998. This was on the L1CAM gene, and was given the name SPG1. Since then more genes have been associated with HSP, and these have been numbered in order of discovery with sequential numbers, with the highest number (so far) being SPG82 identified in 2019 (https://www.omim.org/entry/618770#1). However, there is also a set of genes being identified which are associated with HSP, but which are not being given SPG numbers (for example, RNF170: https://www.genomemed.org/news/2019/10/28/new-gene-for-hereditary-spastic-paraplegia). The picture gets more complicated because there is genetic overlap between HSP (when considered as a whole) and Ataxia, ALS, Alzheimer's and Parkinson's.

An interesting question is: how many different HSP genes might there be? Different researchers have different ideas. Evan Reid suggested in 2014 that there may be 100-200 genes in total (https://hspjourney.blogspot.com/2014/08/agm-hsp-research-historical-perspective.html).

The paper: Perspectives on the Genomics of HSP Beyond Mendelian Inheritance by Dana M. Bis-Brewer and Stephan Züchner, (https://www.frontiersin.org/articles/10.3389/fneur.2018.00958/full) published in 2018 describes several key features. The text below is summary extracts of the paper (I basically copied the whole paper in and retained the parts I wanted to!):

It is usually assumed that eventually nearly all HSP patients will receive a single-gene diagnosis and the diagnostic yield of multigene panels has never been higher (albeit hindered by an increasing burden of Variants of Uncertain Significance).

However, most recently discovered HSP genes are rare causes of the disease affecting few people, and recent multi-patient gene testing studies have had less than 50% success rate in identifying an HSP gene. There is concern of a persisting diagnostic gap, estimated at 30–40%, and even higher for sporadic cases. Gene therapies may soon come to HSP, but these require a specific genetic diagnosis, which emphasises the need to fill the diagnostic gap, illustrated below: 

This gap may not be fully closed by classic Mendelian approaches. There are a number of strategies for identifying further Mendelian and non-Mendelian causes of HSP:

• Systematic reanalysis of unresolved cases can reveal new causative variants. The search should ideally be expanded beyond mutations in the protein-coding regions, but this requires whole-genome sequencing; 
• Another contributor of genome variability that could help resolve the diagnostic gap is structural variation, including copy number variations (CNVs), translocations, and inversions. CNVs are known to play an important role in HSPs, however determining whether a CNV is benign or pathogenic remains a considerable clinical challenge.
• Standard clinical genomic analysis focuses on typical modes of inheritance and unusual inheritance modes are often ignored. Inclusion of these can lead to successful identification of overlooked molecular diagnoses.
• Traditional Mendelian disease analysis are focused on specific alleles. These locus-specific studies disregard a more comprehensive genetic model for human disease in which variants of varying effect size as well as environmental influences contribute to disease.
• Contrary to general expectations for HSP families, asymptomatic carriers are not infrequent.
• Sex-dependent penetrance is suspected in some HSPs based on the excess of affected males.
• Given the high clinical variability observed across HSP patients, genetic modification of the primary allele has been anticipated.
• Exceptions to the fundamental “one gene, one phenotype” may occur. Here the primary allele is sufficient to cause disease, but a secondary allele is a “modifier” that controls aspects like disease severity or progression.
• The current classification systems suggest that HSPs are a distinct and isolated disorder, when in fact HSPs exist on a spectrum between inherited ataxias and Charcot-Marie-Tooth disease.
• These approaches increasingly require larger datasets which contradicts, of course, the low prevalence of rare disease. Raw genetic data aggregation may be the next frontier for HSP gene discovery.
• Gene therapy may soon be applied to specific HSP genes. These novel therapeutic approaches include gene replacement, antisense oligonucleotides (ASO), and soon gene editing. Most require a specific genetic diagnosis.