Abstract Details

Title Mutational Analysis of Known ALS Genes in a Large Italian Population-based Cohort

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S35 - Amyotrophic Lateral Sclerosis (3:42 PM-3:54 PM)

Poster/Presentation
Number 002

Objective To delineate the genetic architecture of ALS in the Italian population, we sequenced the whole genome of a large ALS cohort. We aimed to identify potential disease-causing variants and to assess the burden of rare genetic variants in ALS genes.

Background The relevance of variants in ALS genes is not always clear. A detailed understanding of their contribution to disease burden may help guide clinical and research efforts.

Design/Methods Whole-genome data and repeat expansion PCR of C9orf72 were generated for 959 ALS patients from the Piemonte ALS Register and 677 controls. We analyzed a panel of 45 ALS genes: coding, non-synonymous and loss-of-function variants were regarded as disruptive. Rare variants were retained, considering a minor allele frequency of 3 × 10-5. We performed burden tests to assess for an excess of variants at gene level.

Results A significant portion of our cohort (n = 187, 19.5%) carried potential disease-causing variants. Of these, 71 patients (7.4%) carried the C9orf72 repeat expansions. An additional 34 (3.6%) cases carried mutations known to be causative. The prevalence of patients with mutation is higher than previously reported in both familial (n = 69, 65.1%) and sporadic cases (n = 118, 14.0%). Burden tests demonstrated a strong association for SOD1, which is the second most common cause of the disease in our cohort. A lower signal was observed for TARDBP. No other gene surpassed the threshold for significant association.

Conclusions We present a genome-wide, population-based study of ALS: our results confirm the genetic pleiotropy of the disease and suggest that the true rate of genetic Italian ALS cases is higher than previously described. Our data highlight the benefits of whole-genome sequencing as a diagnostic and research tool for ALS: the availability of rich phenotypic information will allow us to increase our confidence in pathogenicity of discovered variants.

Authors/Disclosures
Maurizio Grassano, MD (Dept. of Neuroscience, University of Turin) PRESENTER	Dr. Grassano has received research support from American Brain Foundation, ALS Association and ��ɫ��.
Andrea Calvo, MD, PhD, FAAN (Dept. of Neuroscience, University of Turin)	Dr. Calvo has nothing to disclose.
Sonja W. Scholz, MD, FAAN (National Institute of Neurological Disorders and Stroke)	Dr. Scholz has received personal compensation for serving as an employee of National Institutes of Health. An immediate family member of Dr. Scholz has received personal compensation for serving as an employee of National Institutes of Health. The institution of Dr. Scholz has received research support from National Institutes of Health. The institution of an immediate family member of Dr. Scholz has received research support from National Institutes of Health. An immediate family member of Dr. Scholz has received intellectual property interests from a discovery or technology relating to health care. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Council Member with Lewy Body Dementia Association that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Editorial Board Member with JAMA Neurology that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Editorial Board Member with Journal of Parkinson's Disease that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Board Member with Mission MSA that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Board Member with The GBA1 Canada Initiative (G-Can) that is relevant to AAN interests or activities.
Bryan Traynor, MD (National Institute on Aging)	The institution of Dr. Traynor has received research support from ALS Association. The institution of Dr. Traynor has received research support from Merck. The institution of Dr. Traynor has received research support from Myasthenia Gravis Foundation. The institution of Dr. Traynor has received research support from Cerevel Therapeutics. Dr. Traynor has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file

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