Background: Amyotrophic Lateral Sclerosis (ALS) is a complex genetic condition The Irish ALS Register has been in operation for over 30 years, with full ascertainment of all those diagnosed since 1995.Heritability accounts for approximately 50% of risk at population level. Research oriented genetic surveillance aligned with ProjectMinE has been in operation since 2008,and commercial genetic testing has been offered to all patients since 2022. Up 15% of those diagnosed have a family history of the disease, and that the repeat expansion in C9orf72 accounts for approximately 10% of all cases, and 50% of those with a known history of familial ALS. To date, no systematic collation of the genetic landscape of non-C9orf72 related familial ALS has been undertaken.
Aims: Using the Irish ALS Register, including genetic data from commercial testing and genetic surveillance within a research setting, (1) to characterise the genetic landscape of ALS in Ireland, (2) to construct detailed pedigrees of those with familial ALS associated with known variants (3) to identify extended kindreds with ALS from whom a genetic variant has not been identified (4) to identify and forward for whole genome sequencing DNA samples from informative kindreds for whom no known variant has been identified to date.
Hypothesis: The genetic landscape of ALS in Ireland differs from other countries, and interrogation will provide new insights into familial ALS in Ireland.
Methods: Data will be collated from the Irish ALS Register, which includes clinical characteristics and the results of commercial genetic testing from all consenting patients. Genetic data collected for research purposes will be accessed and incorporated into the analysis. Informative pedigrees with no identified causative variant, and from whom DNA is available from at least 3 affected members will be selected for whole genomic sequencing.
Data will be collated and presented at international peer reviewed meetings.