Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder

Hum Mol Genet. 2016 Feb 1;25(3):546-57. doi: 10.1093/hmg/ddv495. Epub 2015 Dec 8.


De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Base Sequence
  • Child
  • DNA / genetics
  • DNA / metabolism
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / metabolism
  • Developmental Disabilities / pathology
  • Exome
  • Female
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypertelorism / genetics*
  • Hypertelorism / metabolism
  • Hypertelorism / pathology
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Intellectual Disability / pathology
  • Language Development Disorders / genetics*
  • Language Development Disorders / metabolism
  • Language Development Disorders / pathology
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Protein Binding
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Transcription, Genetic


  • FOXP1 protein, human
  • FOXP2 protein, human
  • Forkhead Transcription Factors
  • Repressor Proteins
  • DNA