Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia

Michaela Pogoda; Franz-Joachim Hilke; Ebba Lohmann; Marc Sturm; Florian Lenz; Jakob Matthes; Francesc Muyas; Stephan Ossowski; Alexander Hoischen; Ulrike Faust; Ilnaz Sepahi; Nicolas Casadei; Sven Poths; Olaf Riess; Christopher Schroeder; Kathrin Grundmann

doi:10.3389/fneur.2019.01332

Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia

Front Neurol. 2019 Dec 18:10:1332. doi: 10.3389/fneur.2019.01332. eCollection 2019.

Authors

Michaela Pogoda¹, Franz-Joachim Hilke^{1

2}, Ebba Lohmann^{3

4

5}, Marc Sturm¹, Florian Lenz¹, Jakob Matthes¹, Francesc Muyas^{1

6

7}, Stephan Ossowski^{1

6

7}, Alexander Hoischen^{8

9}, Ulrike Faust¹, Ilnaz Sepahi¹, Nicolas Casadei^{1

10}, Sven Poths¹, Olaf Riess^{1

10}, Christopher Schroeder¹, Kathrin Grundmann¹

Affiliations

¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
² Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³ Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁴ Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
⁵ German Center for Neurodegenerative Diseases, Tübingen, Germany.
⁶ Bioinformatics and Genomics Program, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
⁷ Universitat Pompeu Fabra, Barcelona, Spain.
⁸ Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
⁹ Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
¹⁰ DFG NGS Competence Center Tübingen, Tübingen, Germany.

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.

Keywords: ATM; MIPs; NGS; ataxia-telangiectasia; dystonia.