Why genetic diagnosis rates still so low in HSP

Limitations of genetic testing technology

Dr Craig Blackstone

Dr Craig Blackstone, a global authority on the HSPs, concludes that a limitation of whole exome sequencing (WES) is likely responsible for a larger percentage of unidentified cases of HSP than other possible reasons.

WES is the most commonly employed technology in the new age of genetic testing, however WES is not able to identify certain classes or types of mutations. Dr Blackstone thinks this is likely to be a much more important reason for unidentified cases than where mutations are identified but their disease significance is unclear; or where the clinical diagnosis of HSP is inaccurate; or where new HSP genes are yet to be identified.

Dr Blackstone states the need for whole genome sequencing (WGS) combined with RNA sequencing approaches as the pathway to significant improvement in genetic diagnosis for the HSPs.


Hereditary spastic paraplegias (HSPs) are genetically and clinically diverse inherited neurological disorders afflicting about 2 to 9 per 100,000 individuals across different populations. These typically progressive disorders share the cardinal feature of lower extremity spasticity and resulting gait disturbance, due to a length‐dependent axonopathy of corticospinal motor neurons. This lower extremity spasticity can occur with other neurological or non‐neurological symptoms (complex forms of HSP) or in relative isolation (pure HSPs). HSPs can have symptom onset across a wide range from infancy to old age, though early adulthood is common for many forms.1

A remarkable feature of these disorders is the very large number of genetic disease loci that have been identified, denoted SPG1 to SPG80 (sequentially in order of identification) plus others. Most of these identifications have been made within the past two decades, particularly after the advent of whole exome sequencing (WES), and they encompass all types of inheritances.2  Over 60 genes have now been identified as causative, with the mutated gene products predicted to coalesce into a relatively small number of common cellular pathogenic themes that are guiding new therapeutic investigations.1 Historically, HSPs have been under-diagnosed, though as genetic testing has become more affordable and widely employed, diagnostic accuracy has improved.

Schiavoni et al.3 analyze retrospectively their experience with patients diagnosed with HSP at a child neurology center in Northern Italy over a nearly 30‐year period. Many other HSP case series have been published from leading centers throughout the world, and comparisons among these studies are often insightful, particularly for clarifying key genotype‐phenotype correlations. For instance, Schiavoni et al. found in their pediatric early‐onset cohort (from a geographical area with limited consanguinity) that autosomal dominant SPG3A was the most common form,3 consistent with previous studies reporting that SPG3A is the most common childhood‐onset HSP; in older cohorts autosomal dominant SPG4 is much more common.2

Furthermore, this study identifies new mutations in known and novel genes — some mutated in other neurological disorders — where pathogenicity remains unclear, awaiting definitive functional studies or additional patients. This latter point emphasizes a persistent challenge in the diagnosis of HSPs; there are still many variants of unclear significance, since time‐consuming functional and mechanistic studies usually lag the more rapid identification of new variants.

Despite the expertise of the authors, the establishment of a genetic diagnosis in patients with suspected HSP in this series is only about 36%, in line with other studies reporting gene identifications in 30% to 60% of those with clinically suspected HSP.3 One might ask why, with so many known genes, is this percentage not higher? First, it seems certain that there are more genes to be identified; even so, new gene identifications have mostly plateaued after a rush of new genes were uncovered as WES became commonplace over the last decade, and most new HSP genes are mutated in only a very small number of patients. Thus, new genes, or at least those identified using current approaches, likely represent a small fraction of undiagnosed cases. Of course, some variants of unclear significance will also ultimately be found to be pathogenic. Some patients may have diagnoses other than HSP, though this also is expected to be a small percentage. Rather, it seems increasingly likely that types of mutations in known genes that are not identified using WES approaches (such as changes in introns or cryptic splice variants) may comprise a larger percentage of the unidentified cases. Thus, WES will need to be supplanted by whole genome sequencing combined with transcriptome sequencing (RNA‐seq) approaches.4 A genetic diagnosis will increasingly be crucial for patients with HSP, since emerging therapies will likely target specific HSP subtypes.

SOURCE: https://doi.org/10.1111/dmcn.14564

Earlyonset hereditary spastic paraplegia: the possibility of a genetic diagnosis

Craig Blackstone

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

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