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

Morison, Lottie D; Meffert, Elisabeth; Stampfer, Miriam; Steiner-Wilke, Irene; Vollmer, Brigitte; Schulze, Katrin; Briggs, Tracy; ... Morgan, Angela T; + view all (2022) In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2. Journal of Medical Genetics 10.1136/jmg-2022-108734. (In press). Green open access

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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.

Type: Article
Title: In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/jmg-2022-108734
Publisher version: http://dx.doi.org/10.1136/jmg-2022-108734
Language: English
Additional information: 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/.
Keywords: Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, genotype, genetics, phenotype, paediatrics, DEVELOPMENTAL SPEECH, CHILDHOOD APRAXIA, LANGUAGE IMPAIRMENT, CHILDREN, DELETION, GENE, DISORDERS, MOTHER, 7Q31, EXPRESSION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10161495
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