Objective: We applied a genetic panel targeting genes causative of NDDs, but we also included several risk factor genes, to assess the efficacy of a targeted NGS panel as an effective tool to create a more detailed genetic profile for patients and to highlighting the role of NGS in uncovering pleiotropic events in NDDs.

Background: The clinical diagnosis of NDDs based on phenotype is difficult in heterogeneous conditions with overlapping symptom. Some of the disorders are associated with mutations in a single gene such as SCA, HSP, CMT; the others such as AD, FTD, or PD were defined as complex genetic disorders and several different gene loci could play role in their onset. The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. NSG has been very successful in this regard because it confers the advantage of detecting variants in all genes simultaneously with a highly sensitivity.

Method: Using the NGS panel, designed to sequence the encoding area of 34 genes related to NDDs manifesting with movement and cognitive disorders, we performed a mutation screening of the DNA of 86 Italian patients with early-onset (<60 years) movement disorders and cognitive and/or behavioural disturbances with or without familial history for NDDs.

Results: We detected 34 known causative mutations, novel and potentially pathogenic variants in approved and possible candidate disease genes, risk factors, and modifiers in 30 patients (26%). We found 17 patients carrying more than one potentially disease-causing variant, suggesting the hypothesis that NDDs might be of complex genetic origin. Our data have revealed pleiotropic events, reinforcing the notion that some neurodegenerative diseases are part of pathological spectrums arising from common molecular processes.

Conclusion: The majority of patients with these disorders are sporadic with unknown etiology, probably involving a combination of genetic and environmental risk factors. The observation of pleiotropy suggests that common pathological mechanisms may underlie clinically diverse neurological syndromes. With NGS, genetic diagnosis is already replacing phenotype-oriented classification of neurological disorders, and individualized treatment based on genetic findings may one day be available to treat neurodegenerative diseases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeted-ngs-of-genes-related-to-hereditary-and-sporadic-ndds-and-movement-disorders-in-italian-cohort/