Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities

Lot Snijders Blok*, Arianna Vino, Joery den Hoed, Hunter R. Underhill, Danielle Monteil, Hong Li, Francis Jeshira Reynoso Santos, Wendy K. Chung, Michelle D. Amaral, Rhonda E. Schnur, Teresa Santiago-Sim, Yue Si, Han G. Brunner, Tjitske Kleefstra, Simon E. Fisher*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Web of Science)

Abstract

Purpose Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. Methods We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants. Results We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein. Conclusion Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.

Original languageEnglish
Pages (from-to)534-542
Number of pages9
JournalGenetics in Medicine
Volume23
Issue number3
Early online date28 Oct 2020
DOIs
Publication statusPublished - Mar 2021

Keywords

  • DE-NOVO MUTATIONS
  • EXPRESSION
  • FORKHEAD-DOMAIN
  • FOXP4
  • GENE
  • IDENTIFICATION
  • INDIVIDUALS
  • MISSENSE MUTATIONS
  • PULMONARY
  • SPEECH
  • SUBFAMILY
  • congenital diaphragmatic hernia
  • de novo variants
  • language disorder
  • neurodevelopmental disorder
  • speech
  • HUMAN SPEECH

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