De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals.
The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) in non-neuronal cells.
Type of Disorder
The contribution of de novo coding mutations to autism spectrum disorder.