Monoallelic and Biallelic FOXP4 Variants Cause Short Stature, Dysmorphic Features, Neurodevelopmental, Heart, and Congenital Abnormalities

FOXP4 is a transcription factor belonging to the FOX subfamily P, which acts as a multifunctional regulator in cardiac morphogenesis, lung development, and gut development. Six heterozygous missense and loss-of-function (LoF) variants in FOXP4 were reported in a few cases to cause neurodevelopmental phenotypes with multiple congenital abnormalities. Larger studies are needed to further confirm and delineate FOXP4-related disease. In this study, exome/genome sequencing was used to identify variants in 13 participants with short stature, dysmorphic features, neurodevelopmental disorders (NDD), and congenital heart disease (CHD). Additionally, we reviewed the data of 12 published cases. Among 25 participants with FOXP4 variants, 23 carried heterozygous variants, and two were homozygous for LoF variants. Most cases presented with short stature, failure-to-thrive, and dysmorphic features. Other common features included NDD, skeletal anomalies, and CHD. All heterozygous variants recruited in this study were absent from controls, confirmed to be de novo or inherited from affected parents, and predicted to undergo nonsense-mediated decay (NMD) or disrupt canonical splicing. The two homozygous LoF variants were predicted to undergo NMD. This study provides clinical and genetic evidence to confirm the autosomal dominant disease and characterizes the recessive form of FOXP4-related disease.