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https://hdl.handle.net/2440/137082
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Type: | Journal article |
Title: | In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2 |
Author: | Morison, L.D. Meffert, E. Stampfer, M. Steiner-Wilke, I. Vollmer, B. Schulze, K. Briggs, T. Braden, R. Vogel, A. 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. et al. |
Citation: | Journal of Medical Genetics, 2023; 60(6):597-607 |
Publisher: | BMJ Publishing Group |
Issue Date: | 2023 |
ISSN: | 0022-2593 1468-6244 |
Statement of Responsibility: | Lottie D Morison, Elisabeth Meffert, Miriam Stampfer, Irene Steiner-Wilke, Brigitte Vollmer, Katrin Schulze, Tracy Briggs, Ruth Braden, Adam Vogel, Daisy Thompson-Lake, Chirag Patel, Edward Blair, Himanshu Goel, Samantha Turner, Ute Moog, Angelika Riess, Frederique Liegeois, David A Koolen, David J Amor, Tjitske Kleefstra, Simon E Fisher, Christiane Zweier, Angela T Morgan |
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, 'th', 'r', 'ch', '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. |
Keywords: | genetics genotype paediatrics phenotype |
Description: | Published June 2023 |
Rights: | © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
DOI: | 10.1136/jmg-2022-108734 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1116976 http://purl.org/au-research/grants/nhmrc/1127144 http://purl.org/au-research/grants/nhmrc/1195955 |
Published version: | http://dx.doi.org/10.1136/jmg-2022-108734 |
Appears in Collections: | Medicine publications |
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hdl_137082.pdf | Published version | 700.07 kB | Adobe PDF | View/Open |
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