A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment

Eur J Hum Genet. 2015 Dec;23(12):1702-7. doi: 10.1038/ejhg.2015.66. Epub 2015 Apr 8.


FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency.

Publication types

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

MeSH terms

  • Adolescent
  • Autistic Disorder / diagnosis
  • Autistic Disorder / genetics*
  • Female
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • HEK293 Cells
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Language Disorders / diagnosis
  • Language Disorders / genetics*
  • Mutation*
  • Protein Transport
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Syndrome


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