In the September issue of Brain, Mathieu Barbier and Isabelle Le Ber from Paris Brain Institute report the finding of a X-linked modifier of the age at onset in the C9orf72 disease “SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration”.
The pathogenic G4C2 repeats expansion is a major cause of hereditary frontotemporal dementia (FTD) as well as amyotrophic lateral sclerosis (ALS). Carriers of this expansion often present with a highly variable phenotype including heterogeneous clinical picture and variable age at onset. Indeed, patients can develop symptoms from the third decade of life to nearly incomplete penetrance in elderly carriers. To date, this phenotypical variability is poorly understood.
In this work, Mathieu Barbier and Dr. Isabelle Le Ber (Durr/Stevanin’ team) pursued their investigations in the field through Genome Wide Association Studies (GWAS). To get around the problematic of rare diseases which subsequently limits the size of cohorts, they included relatives, all carriers of the C9orf72 pathogenic expansion, with either highly concordant or discordant age at onset. This design was actually used in pioneer genetic studies in which the inclusion of highly informative relatives was privileged. Through this discovery cohort and multiple waves of replications with unrelated individuals from different international consortia, and the use of different statistical methodologies, the authors highlighted a polymorphism robustly associated with the age at onset. This polymorphism (rs1009776) lies on chromosome X, upstream of the gene SLITRK2 encoding for a post-synaptic transmembrane protein involved in the development of excitatory synapses.
In addition, they performed functional studies on brain tissue from C9orf72 expansion carriers with different rs1009776 genotypes. In particular the synaptic vesicular pathway, which is known to be affected in the C9orf72 pathology seems to be more preserved in patients carrying the allele associated with a late onset conversely to the others.
Thus, this work is original in several ways:
- First, the original GWAS design including highly informative relatives. This design could be of interest especially in the context of rare diseases.
- Second, the highlighting of an X-linked modifier (the X-chromosome being often neglected in GWAS although it carries about 800 genes).
- Third, from the identification of this modifier and subsequent functional investigations, results suggest that preservation synaptic vesicular pathway may delay the appearance of symptoms in C9orf72 expansion carriers.
SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration. Mathieu Barbier, et al. Brain, Volume 144, Issue 9, September 2021, Pages 2798–2811