De novo <i>PHIP</i>-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features

Abstract

Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (<i>PHIP</i>) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in <i>PHIP</i> has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including <i>PHIP</i>, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations. <i>PHIP</i> produces multiple protein products, such as PHIP1 (also known as DCAF14), PHIP, and NDRP. PHIP1 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 ubiquitin ligase complex. CUL4B deficiency has been associated with intellectual disability, central obesity, muscle wasting, and dysmorphic features. The overlapping phenotype associated with CUL4B deficiency suggests that <i>PHIP</i> mutations cause disease through disruption of the ubiquitin ligase pathway.