Background Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.
Methods We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.
Results Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.
Conclusions FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype–phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.
- intellectual disability
- language impairment
- oromotor dysfunction
- genotype-phenotype correlation
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Contributors We hereby declare that all authors have contributed to this work: IM and BCa contributed to the conception and design of the article, data acquisition, analysis and interpretation of the clinical, molecular and functional data, and writing of the manuscript. DL contributed to the conception and design of the article and to the acquisition of clinical and molecular patient data. DR, GAR, FFH, JLM and PAD contributed to the acquisition of the functional data, and analysis and interpretation of these data. NRe, JP, CC, JM, JR, NRa, SGM, PL, MPB, MÁM, StM, VB, SM, NB, AO, OV, MV, TJLdR, DM, JS, KKV, NDD, AKHK, LH, BD, AN, LT, JA, MJP, KN, BCe, A-SS, DP, MaH, MiH, MB, AD and BM contributed to the acquisition of clinical and molecular patient data. All authors have approved the manuscript and none have reported a conflict of interest.
Funding BCa is a Senior Clinical Investigator, funded by Fund for Scientific Research Flanders (FWO). This project was cofunded by FWO project G044615N and Czech grants 00064203 and NF-CZ11-PDP-3-003-2014.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Commissie voor Medische Ethiek Universitair Ziekenhuis Gent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This study makes use of data generated by the DECIPHER Consortium. A full list of centres who contributed to the generation of the data is available from and via email from firstname.lastname@example.org. Funding for this project was provided by the Wellcome Trust.
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