FOXP2 – Childhood Apraxia of Speech

FOXP2 is a forkhead-box transcription factor critical for development of neural circuits underlying speech and language. Heterozygous disruption of FOXP2 leads to childhood apraxia of speech (CAS), a severe motor‐speech disorder characterized by impaired planning and programming of speech movements. FOXP2 haploinsufficiency most commonly arises from inherited or de novo coding variants, with clinical onset in early childhood.

Genetic evidence includes 28 individuals with pathogenic FOXP2 variants (12 loss-of-function, 5 missense) identified across 17 families, all presenting with CAS ([PMID:36328423]). Variants include recurrent missense changes such as c.1658G>A (p.Arg553His) that segregate with affected status. Mosaic FOXP2 deletions have also been reported, including a 14.8-Mb mosaic 7q31 deletion involving FOXP2 detected by array CGH in a patient with CAS ([PMID:22144704]).

Segregation analyses demonstrate absence of paternal FOXP2 in 12 affected relatives from Silver-Russell syndrome patients with maternal uniparental disomy or deletions, confirming parent-of-origin haploinsufficiency as causative for CAS ([PMID:17033973]). In a large three-generation family, the c.1658G>A (p.Arg553His) variant co-segregates with CAS in all carriers.

Functional assays support a loss-of-function mechanism: the p.Arg553His substitution disrupts nuclear localization and DNA binding in human neuronal cell lines ([PMID:16984964]); mouse knock-in models carrying the analogous R552H mutation exhibit aberrant striatal activity and motor-skill learning deficits ([PMID:21876543]); and cortical neuron studies reveal increased GABAB/GIRK signaling with reduced dendritic complexity in Foxp2+/R552H mice ([PMID:33020214]).

Together, genetic and experimental data converge on FOXP2 haploinsufficiency as a definitive cause of CAS. Clinical genetic testing for FOXP2 coding variants is recommended in individuals with CAS to inform diagnosis and genetic counseling. FOXP2 variant analysis offers a precise diagnostic entry point and a foundation for future therapeutic strategies.

References

• Pediatrics • 2012 • Mosaic 7q31 deletion involving FOXP2 gene associated with language impairment. PMID:22144704
• Journal of medical genetics • 2023 • In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2. PMID:36328423
• American journal of human genetics • 2006 • Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. PMID:17033973
• Human molecular genetics • 2006 • Functional genetic analysis of mutations implicated in a human speech and language disorder. PMID:16984964
• Molecular psychiatry • 2012 • An aetiological Foxp2 mutation causes aberrant striatal activity and alters plasticity during skill learning. PMID:21876543
• The Journal of neuroscience • 2020 • An Etiological Foxp2 Mutation Impairs Neuronal Gain in Layer VI Cortico-Thalamic Cells through Increased GABAB/GIRK Signaling. PMID:33020214

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