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

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.

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

“…Interestingly, the lead GWAS variant in this locus (rs1886814) is less common in Europeans (gnomAD allele frequency = 2.4%) than in East Asians (37.3%), Admixed Americans (18.9%), or South Asians (11.8%) (Karczewski et al, 2020) and was found to be associated with COVID-19 in East Asians by the COVID-19 HGI (COVID-19 Host Genetics Initiative, 2020, 2021. We found that this GWAS signal colocalized with a lung-specific eQTL for FOXP4, a transcription factor associated with neurodevelopmental disorders and congenital abnormalities with lung cancer (Snijders Blok et al, 2021;Yang et al, 2015). Fine mapping with this lung-specific eQTL signal for FOXP4 identified rs1886814 as the variant with the highest likelihood of causality (PPA = 0.870, Figure 4A), which is located $10 kb upstream of FOXP4 and is likely a regulatory variant whose alternative allele is associated with increased FOXP4 expression (effect size b = 0.46; Table S3).…”

The forkhead box transcription factor FoxP4 regulates thermogenic programs in adipocytes

“…Our studies demonstrating that FoxP4 is present in adipose tissues is novel given that FoxP4 has been mainly reported to be expressed in neuronal, pulmonary, gut, and T cells ( 21 , 28 , 35 , 36 ). More specifically, our data provide new evidence that the basal levels of FoxP4 are selectively enhanced in subcutaneous fat tissue, suggesting a potential distinct role of FoxP4 specifically in this depot.…”

Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

“…Strong genetic evidence indicates that alterations in the NPFs-ARP2/3 signaling module may lead to ID: copy number variants of the chromosomal region 15q11-q13, encompassing CYFIP1 , were identified in patients with ASD and ID [ 243 ], with several studies indicating a pathogenic role for both increased and decreased CYPFI1 dosage [ 244 , 245 , 246 ]; 21 de novo missense CYPFI2 variants, most of which were shown to impact on WRC-mediated actin remodeling, have been reported in 37 ID patients [ 247 , 248 ]; WASHC4 has been identified as an autosomal recessive ID gene [ 249 , 250 ]; NCKAP1 variants predicted to be deleterious for protein function have been associated with ID [ 251 ]; ABI2 is a candidate autosomal recessive ID gene [ 252 ]; de novo splice site mutations of WASHC5 were shown to cause Ritscher–Schinzel/3C syndrome, a disorder characterized by several phenotypes, among which ID [ 253 ].…”