Clinical and genetic characterization of individuals with predicted deleterious PHIP variants

Cold Spring Harb Mol Case Stud. 2019 Aug 1;5(4):a004200. doi: 10.1101/mcs.a004200. Print 2019 Aug.


Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provide better natural history data to assist with medical management and educational and behavioral support.

Keywords: 2-3 toe cutaneous syndactyly; abdominal obesity; aggressive behavior; almond-shaped palpebral fissure; amblyopia; anteverted nares; attention deficit hyperactivity disorder; autism; blurred vision; chronic constipation; chronic fatigue; clinodactyly of the 5th finger; gastroesophageal reflux; generalized neonatal hypotonia; high forehead; intellectual disability; mild; mild global developmental delay; synophrys; thickened helices; thin upper lip vermilion.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Adolescent
  • Child
  • Child, Preschool
  • Developmental Disabilities / genetics
  • Exome / genetics
  • Exome Sequencing / methods
  • Female
  • Frameshift Mutation / genetics
  • Heterozygote
  • Humans
  • Imidazoles
  • Infant
  • Intellectual Disability / genetics
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Muscle Hypotonia / genetics
  • Mutation / genetics
  • Phenotype
  • Transcription Factors / genetics


  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • PHIP protein, human
  • Transcription Factors