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; ... (2023). In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2. Journal of medical genetics, 60(6), pp. 597-607. BMJ Publishing Group 10.1136/jmg-2022-108734

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Human Genetics
UniBE Contributor:	Zweier, Christiane Gertrud
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0022-2593
Publisher:	BMJ Publishing Group
Language:	English
Submitter:	Pubmed Import
Date Deposited:	04 Nov 2022 12:19
Last Modified:	24 May 2023 00:12
Publisher DOI:	10.1136/jmg-2022-108734
PubMed ID:	36328423
Uncontrolled Keywords:	genetics genotype paediatrics phenotype
URI:	https://boris.unibe.ch/id/eprint/174482