Indepth characterization 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), 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by a National Health and Medical Research Council (NHMRC) NHMRC Centre of Research Excellence in Speech and Language Neurobiology (CRE SLANG) 1116976 and NHMRC Project grant APP1127144 awarded to A.T.M. and S.E.F. NHMRC Practitioner Fellowship 1105008 and Investigator grant 1195955 awarded to A.T.M. This work is also supported by the Victorian Governments Operational Infrastructure Support Program. This work was financially supported by the Dutch Research Council grant to T.K. (015.014.036 and 1160.18.320) and Netherlands Organization for Health Research and Development to T.K. (91718310). S.E.F. is supported by the Max Planck Society. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Royal Children's Hospital gave ethical approval for this work (HREC 37353A). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets generated and analysed during this study are not publicly available because participants have not given permission for data to be made public but may be requested from the corresponding author (ATM) who could go back to the participants to request data sharing. Genotypic and phenotypic data were submitted to Decipher.