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

Link: https://pubmed.ncbi.nlm.nih.gov/33110267/

Genet Med
. 2020 Oct 28. doi: 10.1038/s41436-020-01016-6. Online ahead of print.
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 1 2 3, Arianna Vino 4, Joery den Hoed 4, Hunter R Underhill 5, Danielle Monteil 6, Hong Li 7, Francis Jeshira Reynoso Santos 8 9, Wendy K Chung 10, Michelle D Amaral 11, Rhonda E Schnur 12, Teresa Santiago-Sim 12, Yue Si 12, Han G Brunner 13 14 15, Tjitske Kleefstra 13 14, Simon E Fisher 16 17
Affiliations expand
PMID: 33110267 DOI: 10.1038/s41436-020-01016-6
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.

Keywords: FOXP4; congenital diaphragmatic hernia; de novo variants; neurodevelopmental disorder; speech/language disorder.