Abstract
Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) 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 PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, 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. PHIP 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 PHIP mutations cause disease through disruption of the ubiquitin ligase pathway.
Highlights
Pleckstrin homology domain-interacting protein (PHIP; ENSG00000146247), located on Chromosome 6q14.1, was identified as a candidate gene for severe intellectual disability in one child in a study of 100 children with intelligence quotients (IQs) below 50 and their unaffected parents (de Ligt et al 2012)
Genomic Analysis A total of 2522 patients referred to a single clinical genetic diagnostic lab (GeneDx) with developmental delay or intellectual disability were analyzed by whole-exome sequencing (WES)
Using clinical WES, we have identified two unrelated patients with novel de novo heterozygous predicted deleterious variants in the pleckstrin homology domain-interacting protein (PHIP) gene with a common clinical phenotype of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic facial features
Summary
Pleckstrin homology domain-interacting protein (PHIP; ENSG00000146247), located on Chromosome 6q14.1, was identified as a candidate gene for severe intellectual disability in one child in a study of 100 children with intelligence quotients (IQs) below 50 and their unaffected parents (de Ligt et al 2012). PHIP1 ( known as DCAF14) acts as a substrate receptor in a ubiquitin ligase pathway and mediates substrate-specific proteolysis (Lee and Zhou 2007). PHIP variants cause developmental delay and obesity and Weissman 2011). Using whole-exome sequencing (WES), we identified two novel de novo heterozygous predicted deleterious PHIP variants in two unrelated patients with a common phenotype of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features
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