THE GENETIC LANDSCAPE OF HEREDITARY SPASTIC PARAPLEGIA IN CANADA

SPAST

Marked genetic heterogeneity; SPAST is the leading gene (22.5%), followed by SPG7, ATL1, SPG11 and SPG8

This multicentre Canadian cohort (CanHSP registry, 7 centres) analyses 671 patients from 423 families meeting clinical criteria for hereditary spastic paraplegia (HSP), investigated by gene panels (435 individuals) or exome sequencing (485), with CNV detection by ExomeDepth and confirmation by MLPA. A molecular finding was obtained in 426 patients (63.5%): 52.3% HSP-associated, 10.4% HSP-mimicking disorders and 0.7% other diagnoses, with 36.5% remaining unresolved. The most frequent genes were SPAST (22.5%), SPG7 (5.7%), ATL1 (5.2%), SPG11 (3.6%) and SPG8 (3.3%). SPAST, ATL1 and SPG8 were mainly associated with pure HSP, whereas SPG7 and SPG11 more often showed complicated forms, with cerebellar involvement for SPG7 and cognitive and developmental features for SPG11.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A preprint not yet peer reviewed. The most useful figure for the clinic is the share of HSP-mimicking disorders (10.4%): an HSP presentation warrants broad analysis, exome or genome, rather than a query restricted to HSP genes. Over a third of patients remain undiagnosed; the authors mention reanalysis, genome, RNA and long-read sequencing, without data of their own on what these add.

Analysis by Dr Thibaut Benquey