title: De novoPHIP-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 inPHIPhas previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, includingPHIP, 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.PHIPproduces 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 thatPHIPmutations cause disease through disruption of the ubiquitin ligase pathway.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Webster
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Alexander
authors.affiliation: Kennedy Krieger Institute, Baltimore, Maryland 21205, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Desai
authors.affiliation: Kennedy Krieger Institute, Baltimore, Maryland 21205, USA.
authors.forename: Sakkubai
authors.initials: S
authors.lastname: Naidu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Mir Reza
authors.initials: MR
authors.lastname: Bekheirnia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lewis
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;; Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D000070539:Pleckstrin Homology Domains; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C418612:PHIP protein, human
keywords: abdominal obesity; central hypotonia; intellectual disability, mild; mild global developmental delay