In this study, we designed a gene panel based on Nanopore long-read sequencing using adaptive sampling, targeting n = 564 genes associated with Parkinson’s disease (PD) and repeat expansion disorders. We investigated its diagnostic utility in n = 18 patients with (1) pathogenic variants in LRRK2, PRKN, SNCA, and RAB32 (n = 7); (2) idiopathic PD or FTD negative for known genetic causes (n = 3); (3) repeat expansions in ATXN1, ATXN2, ATXN3, C9orf72, DAB1, FGF14, HTT, and TAF1-SVA (n = 8). Three individuals were multiplexed per flow cell, achieving a mean coverage of 24X (SD = ± 9X) per sample.
Ultimately, 17/20 (85%; Clopper–Pearson 95% CI: 62–97%) expected pathogenic variants were identified; i.e., an SNCA triplication and two repeat expansions in C9orf72 and TAF1-SVA were missed. Additional variants in STXBP2, AP4S1, RARS2, ALS2, and CNBP were identified in five patients. Adaptive sampling is a versatile genetic diagnostic tool in neurodegenerative disorders, while enabling cost-effective multiplexing.
Further validation and improvements in bioinformatic analysis are needed. This research was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (TR 1714/4-1 and TR 1714/8-1) and a Heisenberg Grant (TR 1714/7-1) to J.T. A.N.B. and T.G.D. gratefully acknowledge the use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM).
G.S. is supported by the Wolf Chair for Neurodevelopmental Psychiatry, a joint Hospital-University Named Chair between the University of Toronto, UHN, and the UHN Foundation. G.S. received honoraria for educative activities by the International Movement Disorder Society and Merz Pharmaceuticals. TerK would like to acknowledge support from the Global Parkinson’s Genetics Program (GP2) funded by the Aligning Science Across Parkinson’s initiative and implemented by The Michael J.
Open Access funding enabled and organized by Projekt DEAL. These authors contributed equally: André Fienemann, Julia C. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany André Fienemann, Julia C.
Prietzsche, Joshua Laβ, Christoph Much, Susen Schaake, Theresa Lüth, Carolin Gabbert, Meret Möller, Max Borsche, Teresa Kleinz, Alexander Balck, Norbert Brüggemann, Philip Seibler, Christine Klein & Joanne Trinh Department of Neurology, Medical University of Vienna, Vienna, Austria Alexander Zimprich, Elisabeth Stögmann & Theresa König Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada Division of Neurology, University of Toronto, Toronto, ON, Canada Krembil Brain Institute, Toronto, ON, Canada Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, School of Medicine, Koç University, İstanbul, Turkey Department of Neurosciences, College of Medicine-Philippine General Hospital, University of the Philippines Manila, Manila, Philippines Roland Dominic G. Jamora & Gerard Saranza Department of Neurology and Psychiatry, University of Santo Tomas and the CNS-Metropolitan Medical Center, Manila, Philippines Section of Neurology, Department of Internal Medicine, Chong Hua Hospital, Cebu, Philippines Department of Neurosciences, Movement Disorders Clinic, Makati Medical Center, Makati City, Philippines Section for Movement Disorders, Department of Neurology, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany Meret Möller, Max Borsche, Teresa Kleinz, Alexander Balck, Norbert Brüggemann & Christine Klein The authors declare the following competing interests: RDGJ has received travel grants and speakers’ honoraria from Royal Care Super Specialty Hospital, Darya-Varya Laboratoria, and the Philippine offices of AbbVie, Exeltis, HI-Eisai, Innogen, Medichem, Natrapharm, Sun, Torrent, and Vexxa.
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