Cargando…
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 pathogeni...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314088/ https://www.ncbi.nlm.nih.gov/pubmed/36328423 http://dx.doi.org/10.1136/jmg-2022-108734 |
_version_ | 1785067247814836224 |
---|---|
author | Morison, Lottie D Meffert, Elisabeth Stampfer, Miriam Steiner-Wilke, Irene Vollmer, Brigitte Schulze, Katrin Briggs, Tracy Braden, Ruth Vogel, Adam 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 |
author_facet | Morison, Lottie D Meffert, Elisabeth Stampfer, Miriam Steiner-Wilke, Irene Vollmer, Brigitte Schulze, Katrin Briggs, Tracy Braden, Ruth Vogel, Adam 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 |
author_sort | Morison, Lottie D |
collection | PubMed |
description | 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 (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). 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. |
format | Online Article Text |
id | pubmed-10314088 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-103140882023-07-02 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 Braden, Ruth Vogel, Adam 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 J Med Genet Cognitive and Behavioural Genetics 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 (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). 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. BMJ Publishing Group 2023-06 2022-11-03 /pmc/articles/PMC10314088/ /pubmed/36328423 http://dx.doi.org/10.1136/jmg-2022-108734 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/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/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Cognitive and Behavioural Genetics Morison, Lottie D Meffert, Elisabeth Stampfer, Miriam Steiner-Wilke, Irene Vollmer, Brigitte Schulze, Katrin Briggs, Tracy Braden, Ruth Vogel, Adam 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 In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2 |
title | In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
|
title_full | In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
|
title_fullStr | In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
|
title_full_unstemmed | In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
|
title_short | In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2
|
title_sort | in-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting foxp2 |
topic | Cognitive and Behavioural Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314088/ https://www.ncbi.nlm.nih.gov/pubmed/36328423 http://dx.doi.org/10.1136/jmg-2022-108734 |
work_keys_str_mv | AT morisonlottied indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT meffertelisabeth indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT stampfermiriam indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT steinerwilkeirene indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT vollmerbrigitte indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT schulzekatrin indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT briggstracy indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT bradenruth indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT vogeladam indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT thompsonlakedaisy indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT patelchirag indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT blairedward indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT goelhimanshu indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT turnersamantha indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT moogute indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT riessangelika indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT liegeoisfrederique indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT koolendavida indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT amordavidj indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT kleefstratjitske indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT fishersimone indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT zweierchristiane indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 AT morganangelat indepthcharacterisationofacohortofindividualswithmissenseandlossoffunctionvariantsdisruptingfoxp2 |