Abstract
Abstract
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
were 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.