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. 2025 Sep 3;231(1):iyaf120.
doi: 10.1093/genetics/iyaf120.

Functional analysis of human EED variants using Drosophila

Sharri S Cyrus  1   2 , Sònia Medina-Giró  3 , Tianshun Lian  3 , Douglas W Allan  3   4 , William T Gibson  1   2
Affiliations

Functional analysis of human EED variants using Drosophila

Sharri S Cyrus et al. Genetics. .

Abstract

The Polycomb Repressive Complex 2 is an epigenetic reader/writer that methylates histone H3K27. Rare germline partial loss-of-function (pLoF) variants in core members of the complex (EZH2, EED, and SUZ12) cause overgrowth and intellectual disability syndromes, whereas somatic variants are implicated in cancer. However, up to 1% of the general population will have a rare variant in one of these genes, most of which would be classified as variants of uncertain significance (VUS). Towards screening these VUS for partial LoF alleles that may contribute to disease, here we report functional assays in Drosophila to interrogate Embryonic Ectoderm Development (EED) missense variants. We mimicked the amino acid change(s) of EED variants into its Drosophila ortholog, esc, and tested their function. Known likely benign variants functioned wildtype and known pathogenic variants were LoF. We further demonstrate the utility of this calibrated assay as a scalable approach to assist clinical interpretation of human EED VUS.

Keywords: Drosophila melanogaster; Cohen–Gibson syndrome; EED; Polycomb Repressive Complex 2; functional studies; variants of unknown significance.

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Conflict of interest statement

The authors declare no conflict of interest.

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