Genetic, Molecular, and Phentoypic Characterization of the Autism-Associated FOXP1 Syndrome

Poster Presentation
Friday, May 11, 2018: 5:30 PM-7:00 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
J. Buxbaum1, S. De Rubeis2, M. P. Trelles3, R. Lozano4, A. Kolevzon3, E. Drapeau2, P. M. Siper3, A. R. Durkin5, D. Di Marino6 and Y. Frank4, (1)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, (2)Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, (3)Seaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, (4)Icahn School of Medicine at Mount Sinai, New York, NY, (5)Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, (6)Università della Svizzera Italiana, Lugano, Switzerland

Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features.


The goal of the present study is to comprehensively and prospectively characterize the genetic and clinical spectrum of FOXP1 syndrome. In addition, gene expression studies of induced neurons (iNeurons) from patients and sibling controls are being characterized for gene expression and cellular changes.


As of today, genetic and clinical data has been obtained and analyzed from 5 children and adolescents with mutations in FOXP1 and 1 child with a duplication in the gene. Blood samples suitable for reprogramming into induced pluripotent stem cells (iPSC) were collected for 5 children and their unaffected siblings. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1.


We have identified 5 de novo mutations and 1 gene duplication. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. Blood samples were reprogrammed into iPSC for 10 samples (5 cases and 5 unaffacted siblings). iNeurons are being produced and characterized.


This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in ASD and in development across multiple domains of functioning. As the in vitro studies progress, we will learn more about the pathobiology of this autism-associated syndrome.

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See more of: Genetics