Abstract
Background: This study's aim was to investigate a large cohort of dystonia patients for pathogenic and rare variants in the ATM gene, making use of a new, cost-efficient enrichment technology for NGS-based screening.Methods: Single molecule Molecular Inversion Probes (smMIPs) were used for targeted enrichment and sequencing of all protein coding exons and exon-intron boundaries of the ATM gene in 373 dystonia patients and six positive controls with known ATM variants. Additionally, a rare-variant association study was performed.Results: One patient (0.3%) was compound heterozygous and 21 others were carriers of variants of unknown significance (VUS) in the ATM gene. Although mutations in sporadic dystonia patients are not common, exclusion of pathogenic variants is crucial to recognize a potential tumor predisposition syndrome. SmMIPs produced similar results as routinely used NGS-based approaches.Conclusion: Our results underline the importance of implementing ATM in the routine genetic testing of dystonia patients and confirm the reliability of smMIPs and their usability for germline screenings in rare neurodegenerative conditions.
Highlights
Ataxia-telangiectasia (A-T) is a rare autosomal recessively inherited disease usually characterized by ataxia, neuro-motor impairment, ocular or cutaneous telangiectasia, high risk of malignancies and immunodeficiency [1,2,3]
The disease is caused by mutations of the Ataxia telangiectasia mutated (ATM) gene located on chromosome 11q22-23 [6]
Classic A-T is caused by biallelic truncating ATM mutations which lead to a total loss of ATM protein, resulting in an impaired cell cycle [9]
Summary
Ataxia-telangiectasia (A-T) is a rare autosomal recessively inherited disease usually characterized by ataxia, neuro-motor impairment, ocular or cutaneous telangiectasia, high risk of malignancies and immunodeficiency [1,2,3]. The disease is caused by mutations of the Ataxia telangiectasia mutated (ATM) gene located on chromosome 11q22-23 [6]. Classic A-T is caused by biallelic truncating ATM mutations which lead to a total loss of ATM protein, resulting in an impaired cell cycle [9]. Since variants in ATM are known to confer cancer risk in heterozygous carriers [10], and at the same time cause increased sensitivity of the patients to toxic effects of ionizing radiation [4, 5], identifying ATM mutation carriers can be highly relevant for adequate treatment and regular cancer control examinations. This study’s aim was to investigate a large cohort of dystonia patients for pathogenic and rare variants in the ATM gene, making use of a new, cost-efficient enrichment technology for NGS-based screening
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
