Background: The rise of next-generation sequencing (NGS), allowing fast and cheap massive-parallel DNA sequencing, in genetic testing has revolutionized the approach to diagnosis in neurodegenerative diseases. The traditional approach, which considered different neurodegenerative diseases as separated conditions, mainly associated to groups of known canonical genes, has been overturned by the advent of multiple genes and exomes panels. Increasing evidence supports the existence of a close relationship between genetic profiles of different neurodegenerative diseases, further reinforcing the hypothesis of a co-morbidity between these disorders. Materials and methods: In this study, DNA extracted from blood of 63 sporadic ALS patients has been sequenced with a newly-defined customized ‘neurodegenerative panel’ (SureSelect, Agilent), containing classical ALS genes such as SOD1, TARDBP and FUS, together with Parkinsonian genes such as PINK1 and LRRK2, and genes involved in different neuropathies (eg Charcot-Marie-Tooth, Hereditary spastic paraplegia), for a total of 103 genes. DNA-seq was performed using an Illumina MiSeq sequencer and data analysis was performed according to the best practices described for these applications to identify single nucleotide variants and small insertions/deletions. Pathogenic and likely pathogenic mutations have been confirmed via Sanger sequencing. Results: For six patients, mutations in classical ALS genes have been identified. Three patients have mutations in the SOD1 gene, Two with p.G147S and one p.G93D, one in FUS gene p.G302A and two brothers with mutation in VCP gene (p.R191Q). Surprisingly, likely pathogenetic mutations in non-canonical ALS genes such as PINK1, LRRK2, BAG3 and PDYN were also found. These genes have not been reported to be associated to ALS, but associated to Parkinson’s disease and Spinocerebellar Ataxia 23. Two ALS cases have a very rare nucleotide substitution in LRRK2: rs141252946 and p.E1011D, and one presents a mutation in BAG3 gene p.R71W and one in PDYN E192V. Conclusion: These findings support the hypothesis of the existence of a comorbidity between neurodegenerative diseases and strongly highlight the importance of wide genetic screenings on genes not yet associated to the studied disease. It is clear that the old genotype-phenotype view is quite simplistic and the approach to the disease must be changed.
Genetic testing of sporadic ALS patients reveals pathogenetic mutations in non-ALS genes / M. Valente, S. Zucca, I. Palmieri, J. Garau, F. Rey, S. Gagliardi, L. Diamanti, M. Ceroni, C. Cereda. - In: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION. - ISSN 2167-8421. - 18:suppl. 2(2017 Dec), pp. 95-95. ((Intervento presentato al 28. convegno International Symposium on ALS/MND tenutosi a Boston nel 2017.
|Titolo:||Genetic testing of sporadic ALS patients reveals pathogenetic mutations in non-ALS genes|
|Settore Scientifico Disciplinare:||Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica|
|Data di pubblicazione:||dic-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1080/21678421.2017.1371515/0031|
|Appare nelle tipologie:||01 - Articolo su periodico|