Relevance to Autism

A rare de novo loss-of-function (LoF) variant in the FOXP1 gene was first identified in a male patient with autism and non-syndromic ID (PMID 20950788), while additional de novo LoF variants in FOXP1 have been identified in ASD probands from the Simons Simplex Collection (PMIDs 21572417 and 25636768). A fourth ASD-associated de novo LoF variant in FOXP1 was recently identified in a female patient with a history of ASD, mild intellectual disability, and severe speech and language impairment (PMID 25853299). Variants in FOXP1 have also been identified in patients presenting with intellectual disability and significant speech and language deficits (PMID 20848658). Assessment of the clinical features observed in 25 novel and 23 previously reported patients with FOXP1 mutations in Meerschaut et al., 2017 demonstrated that autistic features were observed in 24 of 32 cases (75%). Phenotypic characterization, including gold standard ASD testing, of six novel cases and three previously reported cases with FOXP1 variants in Siper et al., 2017 demonstrated that all nine individuals presented with symptoms of ASD (with two receiving a diagnosis of ASD); other frequently observed phenotypes included intellectual disability (7/9 cases), hypotonia (8/9 cases), dysarthria (9/9 cases), and fine/gross motor coordination deficits (9/9 cases). Additional de novo likely gene-disruptive/protein-truncating variants in FOXP1 were identified in ASD probands from the SPARK cohort and the Autism Sequencing Consortium in Feliciano et al., 2019 and Satterstrom et al., 2020, respectively; furthermore, transmission and de novo association (TADA) analysis in both reports identified FOXP1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified FOXP1 as a gene reaching exome-wide significance (P < 2.5E-06). Assessment of a combined cohort of 22 individuals with pathogenic or likely pathogenic FOXP1 variants consisting of 17 novel individuals and 5 previously reported individuals in Pilar Trelles et al., 2021 found that 5 of the 21 individuals in this cohort for whom psychiatric history was available received a diagnosis of autism spectrum disorder based on expert clinical consensus.

Molecular Function

Transcriptional repressor. Plays an important role in the specification and differentiation of lung epithelium.

External Links

References

Model Summary

Homozygous conditional brain-specific knockout mice display neuroanatomical anomalies in the striatum and hippocampus, as well as altered spontaneous synaptic transmission, and impaired cognitive function and social behavior.

References