Hildonen, M;
Ciolfi, A;
Ferilli, M;
Cappelletti, C;
Al Alam, C;
Amor, DJ;
Barakat, TS;
... Tartaglia, M; + view all
(2025)
Biallelic loss-of-function variants in ZNF142 are associated with a robust DNA methylation signature affecting a limited number of genomic loci.
European Journal of Human Genetics
, 33
pp. 896-903.
10.1038/s41431-025-01876-z.
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Abstract
Biallelic inactivating variants in ZNF142 underlie a clinically variable neurodevelopmental disorder. ZNF142 is a zinc-finger transcription factor with potential roles on chromatin organization, implying a possible association of ZNF142 loss of function with perturbed genome-wide DNA methylation (DNAm) pattern. We performed EPIC array-based methylation profiling of peripheral blood-derived DNA samples from 27 individuals with biallelic ZNF142 inactivating variants, together with 6 heterozygous carriers and 40 controls. A DNAm signature discovery pipeline was applied by using 440 controls for discovery and validation analyses, and a machine-learning model was trained to classify 8 individuals carrying ZNF142 variants of uncertain clinical significance. Analyses directed to explore the genome-wide DNAm landscape in affected individuals revealed 88 differentially methylated probes constituting the minimal informative set specific to ZNF142 loss of function. This reproducible pattern of DNAm changes involved regulatory regions of a small number of genes. The DNAm signature derived from peripheral blood allowed us to diagnose individuals carrying biallelic inactivating ZNF142 variants when applied to fibroblasts. Our findings provide evidence that biallelic loss-of-function ZNF142 variants result in a specific and robust DNAm signature. The identified DNAm pattern suggests occurrence of a methylation disturbance involving a small number of loci that appears to be shared by different cell lineages.
| Type: | Article |
|---|---|
| Title: | Biallelic loss-of-function variants in ZNF142 are associated with a robust DNA methylation signature affecting a limited number of genomic loci |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41431-025-01876-z |
| Publisher version: | https://doi.org/10.1038/s41431-025-01876-z |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | ZNF142; DNA methylation profiling; episignature; classifier; variant classification; VUS validation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10210009 |
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