De novo PHIP-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 (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.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

“…Likewise, the de novo heterozygous truncating variant identified in PHIP in patient #49 with syndromic ID became the likely cause of his NDD after the publication of 2 other patients. 26 We found a de novo heterozygous truncating variant in RORA in patient #50 with ataxia, epilepsy and severe ID. RORA encodes the retinoic-acid orphan receptor alpha expressed in the brain 27 We identified a pathogenic mutation in 4 of 7 patients with NDEG but this number is too small to discuss the efficiency of ME in this clinical context.…”

“…The clinical significance of this result remained briefly uncertain until the publication of an article reporting biallelic variants in UNC80 in patients with a similar phenotype . Likewise, the de novo heterozygous truncating variant identified in PHIP in patient #49 with syndromic ID became the likely cause of his NDD after the publication of 2 other patients …”

A cryptic Tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation

“…BRWD2/ PHIP is highly expressed in human metastatic melanoma and promotes proliferation in this context (De Semir et al 2012). A recent report also identified BRWD2/PHIP mutations in patients with severe intellectual disability (Webster et al 2016). Similarly, mutations in BRWD3 cause an X-linked intellectual disability syndrome in humans, and mutant mice also display neural development defects (Field et al 2007;Cox et al 2010).…”

The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports

“…This gene was deleted in 24 individuals with no to severe developmental delay (11 in subgroup A, 9 in subgroup B, 4 in subgroup R). Three individuals have been described in the literature with most likely loss-of-function variants in PHIP (pleckstrin homology domain interacting protein, MIM*612870) and a comparable phenotype consisting of developmental delay, obesity and dysmorphic features [ 21 , 22 ]. In our full cohort, 25/45 patients (6 in subgroup A, 11 in subgroup B, 2 in subgroup C and 6 in subgroup R) had a PHIP deletion, displayed no to severe developmental delay, and had the following features in common with the three patients with loss-of-function variants: dysplastic ears (10/16), hypotonia (15/19) and strabism (4/12).…”