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.

Beyster Center for Genomics of Psychiatric Diseases University of California San Diego USA

Center for Medical Genetics Ghent University Hospital Ghent Belgium

Centre de Génétique humaine Cliniques Universitaires Saint Luc Université catholique de Louvain Brussels Belgium

Centre de Génétique Humaine Institut de Pathologie et de Génétique Gosselies Belgium

Centre for Human Genetics University Hospital Leuven Leuven Belgium

CHU Sainte Justine Research Center Université de Montreal Montreal Canada

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech

Department of Neurology Pediatric Neurology Antwerp University Hospital Edegem Belgium

Department of Pediatric Nephrology University Hospital Leuven Leuven Belgium

Department of Pediatrics and Child Neuropsychiatry La Sapienza University Rome Italy

Department of Pediatrics Division of Medical Genetics Stanford University School of Medicine California USA

Department of Pediatrics Ghent University Hospital Ghent Belgium

Departments of Medicine and Neurosciences UC San Diego School of Medicine San Diego USA

Genetic Health Service NZ Wellington New Zealand

Institut de Génétique Médicale Hospital Jeanne de Flandre Lille France

Institut für Klinische Genetik Technische Universität Dresden Dresden Deutschland

Instituto de Genética Médica y Molecular Hospital Universitario La Paz IdiPAZ CIBERER ISCIII Madrid Spain

Laboratory of Medical Genetics Bambino Gesù Children's Hospital IRCCS Rome Italy

Montreal Neurological Institute McGill University Montreal Canada

NYS Institute for Basic Research in Developmental Disabilities Staten Island New York USA

Psychiatry Research Laboratory Prof Dr Alexandru Obregia Clinical Hospital of Psychiatry Bercini Romania

Sheffield Clinical Genetics Service Sheffield Children's Hospital Sheffield UK

West Midlands Regional Clinical Genetics Service and Birmingham Health Partners Birmingham Women's Hospital NHS Foundation Trust Birmingham Women's Hospital Edgbaston UK

J Med Genet. 2018 Jan;55(1):72-73. doi: 10.1136/jmedgenet-2017-104579corr1. PubMed

J Med Genet. 2018 Mar;55(3):214. doi: 10.1136/jmedgenet-2017-104579corr2. PubMed

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