Genet Med

. 2020 Oct 28. doi: 10.1038/s41436-020-01016-6. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/33110267/

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 17Affiliations expand

• PMID: 33110267
• DOI: 10.1038/s41436-020-01016-6

Free article

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.