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

Morison LD, 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 DA, Amor DJ, Kleefstra T, Fisher SE, Zweier C, Morgan AT (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Journal of Medical Genetics BMJ Publishing Group

DOI: 10.1136/jmg-2022-108734

Abstract

BackgroundHeterozygous 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. MethodsHere 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. ResultsSpeech 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. ConclusionsAlthough 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.

Authors with CRIS profile

Christiane Zweier Lehrstuhl für Humangenetik

Involved external institutions

Universitätsklinikum Tübingen DE Germany (DE) Murdoch Childrens Research Institute AU Australia (AU) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) SRH Fachhochschule für Gesundheit Gera DE Germany (DE) University of Southampton GB United Kingdom (GB) University College London (UCL) GB United Kingdom (GB) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) The University of Melbourne AU Australia (AU) Oxford University Hospitals NHS Foundation Trust GB United Kingdom (GB) Eberhard Karls Universität Tübingen DE Germany (DE) Royal Brisbane and Women's Hospital AU Australia (AU) Hunter Genetics AU Australia (AU) University of Manchester GB United Kingdom (GB) Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. (MPG) / Max Planck Society for the Advancement of Science DE Germany (DE)

How to cite

APA:

Morison, L.D., Meffert, E., Stampfer, M., Steiner-Wilke, I., Vollmer, B., Schulze, K.,... Morgan, A.T. (2022). In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2. Journal of Medical Genetics. https://dx.doi.org/10.1136/jmg-2022-108734

MLA:

Morison, Lottie D., et al. "In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2." Journal of Medical Genetics (2022).

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