4.7 Article

Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort

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NEUROLOGY
卷 96, 期 4, 页码 E600-E609

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000011209

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资金

  1. Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata) [RF2016-02362405]
  2. Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research [2017SNW5MB]
  3. European Commission's Health Seventh Framework Programme (FP7/2007-2013) [259867]
  4. Joint Programme Neurodegenerative Disease Research (Strength, ALS-Care and Brain-Mend projects) - Italian Ministry of Education, University and Research
  5. Intramural Research Program of the NIH, National Institute on Aging [Z01AG000949-02]
  6. National Institute of Neurologic Disorders and Stroke [1ZIANS003154]

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Our study assessed the burden of rare genetic variants and estimated the contribution of known ALS genes in an Italian population-based cohort through whole genome sequencing. We identified potential disease-causing variants in 11.9% of ALS patients and confirmed the strong association of rare variants in SOD1 with the disease. We also found that the contribution of rare variants in other known ALS genes to disease risk in our cohort is limited.
Objective To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls. Methods We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population. Results A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited. Conclusions We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.

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