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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)
Publ. Version/Full Text DOI PMC
Open Access Hybrid
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Kmt2b ; Allele Frequency ; Dystonia ; Gnomad ; Variant Interpretation
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Journal Movement Disorders
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
Grants 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)
DOI 10.1002/mds.30066
WOS ID 001361100800001
Scopus ID 85210019527
PubMed ID 39569852
Erfassungsdatum 2024-11-22
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