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Homozygous deletion of the epigenetic regulator PHF20 in individuals with neurodevelopmental disorder

ABSTRACT: PHF20 encodes plant homeodomain finger protein 20 (PHF20), a component of the KAT8-containing non-specific lethal (NSL) complex that deposits acetylation on histone H4 to activate gene expression. We report two unrelated individuals with developmental delay, microcephaly and distinctive facial features, in whom exome sequencing and chromosomal microarray analysis revealed a homozygous deletion of PHF20 that segregated with the disease phenotype in their families. Breakpoint junction sequencing revealed an Alu-Alu mediated deletion event. Western blot in cells from an affected individual showed undetectable PHF20, while levels of other NSL complex subunits were unaltered. Transcriptomic and epigenomic analysis revealed significant downregulation of gene pathways related to cell projection and neuronal development, associated with reduced histone H4K16 acetylation at these genes. In conclusion, our data suggest that homozygous deletion of PHF20 leads to a neurodevelopmental syndrome, potentially through targeted epigenetic dysregulation and altered gene expression essential for neuronal development. Identifying additional families with biallelic PHF20 variants will further delineate the phenotypic spectrum, and molecular studies in neuronal cell lines will be essential for understanding the disease mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309878 | GEO | 2025/11/19

REPOSITORIES: GEO

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Methyl-lysine readers PHF20 and PHF20L1 define two distinct NSL complexes

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Loss of PHF20 does not negatively affect deposition of H4K16 acetylation, but does impact the expression of MOF targets

Project description:Protein post-translational modifications transmit signals in part by creating binding sites for effector molecules. This is especially true in epigenetic pathways where histone tails are heavily modified, resulting in the recruitment of molecules that can affect transcription. One such molecule, plant homeodomain finger protein 20 (PHF20), uses a Tudor domain to read dimethyl-lysine residues and is a known component of the MOF histone acetyltransferase protein complex, suggesting it plays a role in the crosstalk between lysine methylation and histone acetylation. We sought to investigate the biological role of PHF20 by generating a knockout mouse. Without PHF20, mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Mechanistically, PHF20 is not required for maintaining the global H4K16 acetylation levels, but instead works downstream in transcriptional regulation of MOF target genes. ChIP sequencing of H4K16ace ChIP DNA from PHF20 knockout and wild type cells using Illumina Solexa Genome Analyzer II single end sequencing protocol.

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