Indepth characterization of a cohort of individuals with missense and loss-of-function variants disruptingFOXP2

Background Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition. Methods Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2 -only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. Results Speech disorders were prevalent (24/26, 92%) and CAS was most common (23/26, 89%), with similar speech presentations across English and German. Speech was still impaired in adulthood and some speech sounds (e.g. ‘th’, ‘r’, ‘ch’, ‘j’) were never acquired. Language impairments (22/26, 85%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (14/27, 52%) and gross (14/27, 52%) motor impairment, anxiety (6/28, 21%), depression (7/28, 25%), and sleep disturbance (11/15, 44%). Physical features were common (23/28, 82%) 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 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 to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entrypoint for examining the neurobiological bases of speech disorder. What is already known on this topic Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition. What this study adds Here we provide the most comprehensive characterisation of individuals with pathogenic FOXP2 variants, almost doubling the number of published families to date. We provide the first cross-linguistic analysis of speech and language across German and English. We show that the phenotype for pathogenic FOXP2 variants remains relatively specific to speech disorder, compared to phenotypes associated with other monogenic conditions involving CAS. How this study might affect research, practice or policy This study guides identification of cases with a FOXP2 -related disorder for a clinical genetic diagnosis, will improve prognostic counselling and lead to better targeted clinical management.