Genetic report abstractGenetic architecture of ALS in Sardinia
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the adult life, characterized by a progressive deterioration of motor function, causing death because of respiratory failure within 2–4 years after onset. In Caucasian population, 90% of patients appear sporadically (sporadic ALS), whereas ∼10% of patients have a family history positive for ALS or frontotemporal dementia (FTD) (familial ALS, FALS). The commonest genes implied in ALS so far are C9ORF72, SOD1, TARDBP, and FUS (Renton et al., 2014), with marked differences between ethnic groups and geographical regions. Examples of this diversity include the virtual absence of SOD1 mutations in Ireland and the Netherlands (Kenna et al., 2013, van Blitterswijk et al., 2012), the extremely high frequency of C9ORF72 repeat expansions in Scandinavia (Majounie et al., 2012, Smith et al., 2013), and the high frequency of OPTN mutations combined with the relative scarcity of C9ORF72 repeat expansions observed in Japan (Konno et al., 2013, Maruyama et al., 2010).
Sardinia, the second largest Mediterranean island, represents a genetic isolate, characterized by a high frequency of autoimmune disorders (such as multiple sclerosis and diabetes mellitus type 1) and monogenic diseases (such a Wilson disease). As might be expected, this population displays decreased genetic and allelic heterogeneity. We and others have reported that ALS patients of Sardinian ancestry have a higher frequency than expected of the TARDBP p.A382T missense mutation and of the rate of familial ALS (Chiò et al., 2011, Orrù et al., 2012). Despite this, the incidence of ALS in Sardinians retrospectively investigated seems to be within the range of European studies (Pugliatti et al., 2013).
In this report, we describe the genetic profile of a larger series of ALS patients of Sardinian ancestry and extend our analysis to include other ALS genes (C9ORF72, SOD1, TARDBP, and FUS).
Section snippets
Patients
All ALS patients of Sardinian ancestry (i.e., defined as subjects with both parents of Sardinian origin) were eligible to be included in the study. Patients were identified between 2008 and 2013 through the Italian ALS Genetic Consortium, which includes 16 ALS centers in Italy (Chiò et al., 2012a). Clinical information, including cognitive status, were collected on all patients. ALS patients met the El Escorial–revised criteria for definite, probable, probable laboratory-supported, or possible
Results
We identified a cohort of 375 ALS cases with Sardinian ancestry, 236 men and 139 women with a mean (standard deviation) age at symptom onset of 61.1 (12.1) years. Ninety-nine patients (26.4%) had bulbar-onset disease, whereas the remaining 276 (73.6%) cases reported spinal onset of symptoms. A positive family history for ALS, FTD, or both was reported in 100 cases (26.7%).
Discussion
In our study of a large cohort of Sardinian ALS patients, a causative genetic mutation was identified in >40% of cases. The most common mutations were the p.A382T missense mutation in TARDBP, the pathogenic repeat expansion of C9ORF72, and the p.G295S missense mutation of TARDBP. Moreover, several patients carried a double mutation, more commonly the combination of C9ORF72 and TARDBP p.A382T missense mutation, and a smaller number were homozygous for TARDBP missense mutations. Overall, detected
Disclosure statement
AC serves on a scientific advisory board for Biogen Idec, Cytokinetics, and Italfarmaco. GB, MP, FM, MGM, MRM, GF, AC, LDP, PO, TBC, DL, AT, UM, AC, CM, AC, MBa, MBr, HAP, AER, MAN, BJT, and GR report no conflicts of interest. The sponsor organizations had no role in data collection and analysis and did not participate to writing and approving the article. The information reported in the article has never been reported elsewhere.
Acknowledgements
We thank the patients and research subjects who contributed samples for this study. This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, 2010, grant RF-2010–2309849), the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement no. 259867), and the Joint Programme—Neurodegenerative Disease Research (Sophia Project, supported by the Italian Ministry of Health, and Strength Project, supported
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GB and MP contributed equally to this work.
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See Supplementary Appendix for the other members of ITALSGEN and SARDINIALS.