Indepth characterization of a cohort of individuals with missense and loss-of-function variants disruptingFOXP2
Authors: Morison Lottie , Meffert Elisabeth , Stampfer Miriam , Steiner-Wilke Irene , Vollmer Brigitte , Schulze Katrin , Briggs Tracy , Braden Ruth , Vogel Adam P. , 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. 
Published: June 2022

AbstractBackgroundHeterozygous disruptions ofFOXP2were 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.MethodsHere we phenotyped 29 individuals from 18 families with pathogenicFOXP2-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.ResultsSpeech 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.ConclusionsAlthough we identify increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences ofFOXP2dysfunction remain relatively specific to speech disorder, as compared to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce thatFOXP2provides a valuable entrypoint for examining the neurobiological bases of speech disorder.What is already known on this topicHeterozygous disruptions ofFOXP2were 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 addsHere we provide the most comprehensive characterisation of individuals with pathogenicFOXP2variants, 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 pathogenicFOXP2variants remains relatively specific to speech disorder, compared to phenotypes associated with other monogenic conditions involving CAS.How this study might affect research, practice or policyThis study guides identification of cases with aFOXP2-related disorder for a clinical genetic diagnosis, will improve prognostic counselling and lead to better targeted clinical management.