Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities.
Genet Med
; 23(3): 534-542, 2021 03.
Article
en En
| MEDLINE
| ID: mdl-33110267
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Anomalías Múltiples
/
Trastornos del Desarrollo del Lenguaje
/
Discapacidad Intelectual
Límite:
Child
/
Humans
Idioma:
En
Revista:
Genet Med
Asunto de la revista:
GENETICA MEDICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Países Bajos