English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

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

MPS-Authors
/persons/resource/persons221838

Snijders Blok,  Lot
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Radboud University Medical Center;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

/persons/resource/persons146129

Vino,  Arianna
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;

/persons/resource/persons212529

Den Hoed,  Joery
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
International Max Planck Research School for Language Sciences, MPI for Psycholinguistics, Max Planck Society;

/persons/resource/persons4427

Fisher,  Simon E.
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

External Resource
No external resources are shared
Fulltext (public)
Supplementary Material (public)
There is no public supplementary material available
Citation

Snijders Blok, L., Vino, A., Den Hoed, J., Underhill, H. R., Monteil, D., Li, H., et al. (2021). Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities. Genetics in Medicine, 23, 534-542. doi:10.1038/s41436-020-01016-6.


Cite as: http://hdl.handle.net/21.11116/0000-0007-4DED-9
Abstract
Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. 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. 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. 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.