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Abstract

Intellectual disability (ID) is a neurodevelopmental disorder manifesting in children before the age of 18, and affects 1.5-2% of the population. It is characterised by a significant impairment of cognitive functioning and adaptive behaviours, and can be classified as mild (IQ 50-70), moderate (IQ >35), or severe (IQ >20). Although many of the exact molecular risk factors contributing to ID are still unknown, there is considerable evidence to support a genetic basis. Large de novo deletions and a nonsense variant disrupting the FOXP1 transcription factor gene have been described in patients with mild to moderate ID and severe speech and language deficits. Whole exome sequencing of 20 parent-child trios with sporadic autism reported a potentially causative de novo truncating mutation in FOXP1 in a severely affected child with evidence for regression, language delay and comorbidity for moderate ID. Functional analysis in cell systems showed that this FOXP1 protein variant mislocalised to the cytoplasm and lost its transcriptional repressor ability. Recently, sequencing of balanced chromosomal abnormalities in patients with autism or other neurodevelopmental disorders revealed disruption of FOXP1 in a subject with global developmental delay, including speech delay. These results are intriguing because FOXP1 is the closest paralogous human gene to FOXP2, a gene associated with rare forms of speech and language disorder. FOXP1 and FOXP2 are expressed in similar neural circuits and directly interact with each other, with the potential to co-regulate downstream targets, including those involved in language development (such as CNTNAP2). Previous sequencing of FOXP1 coding exons in 883 individuals with ID uncovered 8 non synonymous mutations, some of which are predicted to be damaging. In this study, we generated FOXP1 constructs carrying several of these mutations and performed cell based assays to identify their physiological significance. In our analysis we also included synthetic mutations targeting the FOX DNA binding domain in order to investigate nuclear translocation. FOXP1 variants were transfected into human embryonic kidney and neuroblastoma cell lines and the expressed proteins were analysed in terms of size, cellular localisation, transcription factor function and their ability to interact with wild type FOXP1 and FOXP2 proteins. Our findings highlight the importance of performing functional characterisation to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders like ID and speech and language impairment.