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

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.