Identification of the Genetic Cause of Hereditary Primary Lateral Sclerosis (PLS) in a Large French-Canadian Family

Houle G1,2, Leblond CS1,2, Belzil VV2, Spiegelman D2,3, Dion PA2,3,4, Dupré N5, Rouleau GA2,3

1. Human Genetics department, McGill University, Montreal Qc Canada; 2. Montreal Neurological Institute and Hospital, McGill University, Montreal Qc Canada; 3. Neurology and Neurosurgery department, McGill University, Montreal Qc Canada; 4. Pathology and Cellular Biology department of Montreal University, Montreal Qc Canada; 5. Department of Neurological Sciences, Faculty of Medicine, Laval University, Quebec Qc Canada

Primary lateral sclerosis (PLS) is a neurological disorder characterized by progressive spinobulbar spasticity. This rare disease is caused by degeneration of the upper motor neurons (UMN), which causes slow progressive weakness voluntary muscles movement.

The genetic causes of classic PLS remain unknown, however, rare forms of PLS with either an early childhood or juvenile onset has been linked to mutations altering ALS2 gene. Even tough most cases occur sporadically at adult middle age, the Rouleau’s Lab has previously described a large French-Canadian family (PLS1) of 18 individuals, including 8 affected members in two generations with a dominant mode of inheritance and a progressive involvement of UMN degeneration, consistent with PLS phenotype. Furthermore, they have identified a unique locus linked to PLS on chromosome 4 (4ptel-4p16.1) using a 550-marker genome-wide scan based on microsatellite genotyping that covers 10.2 Mb including more than 130 genes. We hypothesize that variation(s) (in coding or non-coding regions) will perfectly segregate with the PLS phenotype delineated in the PLS1 family and will be located in the previously identified linked locus.

More recently, to validate and refine the locus region linked to PLS phenotype, we performed a whole-genome linkage scan using HumanOmniExpress-12 BeadChip from Illumina capturing 733,202 common TagSNP. We found the same candidate region and were able to reduce the size of the linked region of 2 Mb. In order to identify the causative mutation(s) within PLS1 locus, whole genome sequencing was performed on two affected individuals of the PLS1 family who had the greatest genetic distance in order to obtain the minimum number of shared variants. Bioinformatic tools (GATK, Breakdancer, Pindel, IGV) are used in order to highlight different types of variants (single nucleotide variants and structural variants). Such variants will be then filtered to prioritize those used for further analysis (segregation and functional validation).