In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
Background: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. Methods: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. Results: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, â € th', â € r', â € ch', â € j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (11/15, 44%). Physical features were common (22/27, 81%) 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 an 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 with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.
genetics, genotype, paediatrics, phenotype
Vollmer, Brigitte
044f8b55-ba36-4fb2-8e7e-756ab77653ba
18 November 2022
Vollmer, Brigitte
044f8b55-ba36-4fb2-8e7e-756ab77653ba
Vollmer, Brigitte
(2022)
In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2.
Journal of Medical Genetics, [108734].
(doi:10.1136/jmg-2022-108734).
Abstract
Background: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. Methods: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. Results: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, â € th', â € r', â € ch', â € j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (11/15, 44%). Physical features were common (22/27, 81%) 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 an 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 with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.
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jmg-2022-108734.full
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Accepted/In Press date: 9 October 2022
e-pub ahead of print date: 3 November 2022
Published date: 18 November 2022
Additional Information:
Funding Information:
This work was supported by a National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Speech and Language Neurobiology (CRE-SLANG) number 1116976 and NHMRC Project grant number APP1127144, awarded to AM and SEF; NHMRC Practitioner Fellowship number 1105008 and Investigator grant number 1195955 awarded to AM. This work is also supported by the Victorian Government’s Operational Infrastructure Support Program. This work was financially supported by the Dutch Research Council grant to TK (015.014.036 and 1160.18.320) and Netherlands Organization for Health Research and Development to TK (91718310). SEF is supported by the Max Planck Society.
Publisher Copyright:
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
Keywords:
genetics, genotype, paediatrics, phenotype
Identifiers
Local EPrints ID: 483334
URI: http://eprints.soton.ac.uk/id/eprint/483334
ISSN: 0022-2593
PURE UUID: c75fa67c-6797-4e39-99e9-5b1d9e4febca
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Date deposited: 30 Oct 2023 04:17
Last modified: 17 Mar 2024 03:21
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