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This study characterized the genetic causes of hereditary spastic paraplegia (HSP) in 671 Canadian patients from 423 families using gene panel testing and whole-exome sequencing. Molecular diagnoses were achieved in 63.5% of cases, with SPAST being the most common causative gene (22.5%), followed by SPG7, ATL1, SPG11, and SPG8. The research identified variants in 80 genes, revealing significant genetic and clinical heterogeneity, with some genes predominantly causing pure spasticity while others resulted in complex phenotypes involving cerebellar or cognitive features.
Why it matters
This comprehensive genetic analysis of HSP in Canada provides clinicians with valuable information about which genes to prioritize during diagnostic testing and what clinical features to expect with specific genetic variants. The 63.5% diagnostic rate demonstrates both the value of advanced genetic testing and the need for newer sequencing approaches to solve the remaining cases, which could improve patient management and genetic counseling.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders characterized by progressive lower-extremity weakness and spasticity, with or without additional neurological symptoms. Objectives: To characterize the molecular genetic spectrum, inheritance patterns, molecular finding rate, and clinical characteristics of HSP within a multicenter Canadian cohort. Methods: We investigated 671 patients from 423 families who met clinical criteria for HSP identified through the Canadian HSP (CanHSP) registry from 7 medical centers across Canada. Patients were evaluated using known HSP and HSP mimic gene panels, whereas unsolved and more recent patients underwent whole-exome sequencing (WES). 435 individuals underwent gene-panel testing and 485 underwent WES. Copy-number variants (CNVs) were assessed using ExomeDepth, and candidate CNVs using multiplex ligation-dependent probe amplification (MLPA). Results: Molecular findings were identified in 426 of 671 individuals (63.5%): 351 (52.3%) had HSP-associated findings, 70 (10.4%) HSP-mimicking disorders, and five (0.7%) other molecular findings; 245 (36.5%) remained unresolved. Candidate variants were found in 80 relevant genes, 36 of which were HSP-associated genes. The most frequently implicated genes were SPAST (22.5%), SPG7 (5.7%), ATL1 (5.2%), SPG11 (3.6%), and SPG8 (3.3%). Phenotypically, SPAST, ATL1, and SPG8 w[zg1.1]ere predominantly associated with pure HSP, whereas SPG7 and SPG11 more often showed complicated phenotypes, with prominent cerebellar involvement in SPG7 and cognitive and developmental features in SPG11. Conclusion: Patients in CanHSP present with genetic and phenotypic heterogeneity. Reanalysis and complementary approaches, including whole-genome, RNA, and long-read sequencing, may increase diagnostic yield.
Source: THE GENETIC LANDSCAPE OF HEREDITARY SPASTIC PARAPLEGIA IN CANADA