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Indelicato, E. ; Eberl, A.* ; Boesch, S.* ; Lange, L.M.* ; Klein, C.* ; Lohmann, K.* ; Zech, M.

Genome aggregation database version 4-allele frequency changes and impact on variant interpretation in dystonia.

Mov. Disord., DOI: 10.1002/mds.30066 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND: Population-scale databases majorly contribute to variant interpretation. The recently released Genome Aggregation Database (gnomAD) v4 offers a >5-fold increased sample size compared to v2.1.1. Pathogenic variants absent from v2.1.1 are now registered in v4 at a considerable rate. The implications on variant interpretation in dystonia are unknown. METHODS: All curated variants linked to the most common dominant forms of isolated dystonia were extracted from the International Parkinson's Disease and Movement Disorder Society Gene database. We compared variant population-frequencies and gene constraint metrics between gnomAD v2.1.1 and v4. RESULTS: The majority of dystonia-causing variants (192/247, 77.7%) remained absent from the newer gnomAD version. Of 219 variants absent from v2.1.1, 27 (12.3%) appeared for the first time in v4.1, including well-established pathogenic alleles. Gene constraints for GNAL and KMT2B significantly decreased in v4. CONCLUSIONS: A growing number of dystonia-linked alleles are seen in gnomAD v4. The presence in population-scale data does not preclude pathogenicity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Kmt2b ; Allele Frequency ; Dystonia ; Gnomad ; Variant Interpretation
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Zeitschrift Movement Disorders
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen Projekt DEAL
European Joint Programme on Rare Diseases
EJP RD (EJP RD Joint Transnational Call 2022)
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
Else Kroner-Fresenius-Stiftung
Federal Ministry of Education and Research (BMBF)
Free State of Bavaria under the Excellence Strategy of the Federal Government
Laender
German Research Foundation (DFG)
Technical University of Munich-Institute for Advanced Study
Michael J. Fox Foundation
Aligning Science Across Parkinson's Initiative
European Joint Programme on Rare Diseases (ERN-RND)