Clinical and molecular characterization of FOXP1 variants in subjects with neurodevelopmental disorders.

Background: FOXP1 (forkhead-box protein P1) is a member of the FOX transcription factor family essential for embryonic development. FOXP1, highly expressed in the nervous system, regulates molecular pathways required for proper brain development and function. FOXP1 heterozygous mutations and deletions are associated with "Intellectual developmental disorder with language impairment with or without autistic features" (OMIM#613670), a neurodevelopmental condition characterized by intellectual disability, speech and language delay, motor delay, ASD, and mild dysmorphic features. Methods: Two different customized targeted gene panels, one including 74 ID/ASD and a second including the FOXP1/FOXP2/CNTNAP2 genes, were used to screen respectively a cohort of 844 pediatric subjects with Neurodevelopmenatl Disorders (NDDs) and a selected group of 31 pediatric individuals with Specific Language Impairments (SLIs). Results: 10 FOXP1 variants were detected: 4 novel de novo protein truncating and 1 novel frameshift, all predicted to cause haploinsufficiency, 1 novel paternal missense, 1 maternal and previously reported missense, and 3 ultra-rare missense. Segregation analysis is underway for all the missense variants. Even if more than 100 FOXP1 variants with likely clinical significance are reported in literature, for only few of them the actual impact on protein expression and function has been dissected. We are currently performing a functional characterization of the FOXP1 variants in order to evaluate their effects on protein expression and transcription activity. Conclusion: Our work promises to provide new data to improve genotype-phenotype correlation and elucidate the pathogenic mechanisms underlying FOXP1-related conditions.