In-depth characterisation of a cohort of individuals with missense and 
loss-of-function variants disrupting FOXP2

Morison, Lottie; Meffert, Elisabeth; Stampfer, Miriam; Steiner-Wilke, Irene; Vollmer, Brigitte; Schulze, Katrin; Briggs, Tracy; Braden, Ruth; Vogel, Adam P.; Thompson-Lake, Daisy; Patel, Chirag; Blair, Edward; Goel, Himanshu; Turner, Samantha; Moog, Ute; Riess, Angelika; Liegeois, Frederique; Koolen, David A.; Amor, David J.; Kleefstra, Tjitske; Fisher, Simon E.; Zweier, Christiane; Morgan, Angela T.

doi:10.1136/jmg-2022-108734

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In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2

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Fisher, Simon E.
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

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引用

Morison, L., Meffert, E., Stampfer, M., Steiner-Wilke, I., Vollmer, B., Schulze, K., Briggs, T., Braden, R., Vogel, A. P., Thompson-Lake, D., Patel, C., Blair, E., Goel, H., Turner, S., Moog, U., Riess, A., Liegeois, F., Koolen, D. A., Amor, D. J., Kleefstra, T., Fisher, S. E., Zweier, C., & Morgan, A. T. (2023). In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2. Journal of Medical Genetics, 60(6), 597-607. doi:10.1136/jmg-2022-108734.

引用: https://hdl.handle.net/21.11116/0000-000B-3C69-D

要旨

Background
Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition.

Methods
Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2-only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language outcomes with the first cross-linguistic analysis of English and German.

Results
Speech disorders were prevalent (24/26, 92%) and CAS was most common (23/26, 89%), with similar speech presentations across English and German. Speech was still impaired in adulthood and some speech sounds (e.g. ‘th’, ‘r’, ‘ch’, ‘j’) were never acquired. Language impairments (22/26, 85%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (14/27, 52%) and gross (14/27, 52%) motor impairment, anxiety (6/28, 21%), depression (7/28, 25%), and sleep disturbance (11/15, 44%). Physical features were common (23/28, 82%) but with no consistent pattern. Cognition ranged from average to mildly impaired, and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition.

Conclusions
Although we identify increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entrypoint for examining the neurobiological bases of speech disorder.