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. 2025 Feb;40(2):357-362.
doi: 10.1002/mds.30066. Epub 2024 Nov 21.

Genome Aggregation Database Version 4-Allele Frequency Changes and Impact on Variant Interpretation in Dystonia

Elisabetta Indelicato  1   2   3 , Anna Eberl  1 , Sylvia Boesch  1 , Lara M Lange  4   5 , Christine Klein  4   5 , Katja Lohmann  4 , Michael Zech  2   3   6
Affiliations

Genome Aggregation Database Version 4-Allele Frequency Changes and Impact on Variant Interpretation in Dystonia

Elisabetta Indelicato et al. Mov Disord. 2025 Feb.

Abstract

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.

Keywords: KMT2B; allele frequency; dystonia; gnomAD; variant interpretation.

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