Prospective investigation of FOXP1 syndrome

• DOI: 10.1186/s13229-017-0172-6
• Publication Date: 2017-10-24T14:36:50Z
• Authors: Paige M. Siper; Silvia De Rubeis; Maria del Pilar T...; Allison Durkin; Daniele Di Marino; François Muratet; Yitzchak Frank; Reymundo Lozano; Evan E. Eichler; Morgan Kelly; Jennifer Beighley; Jennifer Gerdts; Arianne S. Wallace; Heather C. Mefford; Raphael A. Bernier; Alexander Kolevzon; Joseph D. Buxbaum
• Keywords: Male; Adolescent; Autism Spectrum Disorder; Developmental Disabilities; Mutation, Missense; 03 medical and health sciences; Intellectual Disability; Humans; Amino Acid Sequence; Genetic Testing; Prospective Studies; RC346-429; Child; Language Disorders; 0303 health sciences; Polymorphism, Genetic; Research; Forkhead Transcription Factors; DNA; Protein Structure, Tertiary; 3. Good health; Phenotype; Child, Preschool; Female; Neurology. Diseases of the nervous system; Protein Binding

Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying mutations and deletions have described presence autism spectrum (ASD) traits, intellectual disability, language impairment, psychiatric features. The goal present study was comprehensively characterize genetic clinical This is first prospectively examine genotype-phenotype relationship multiple with syndrome, using battery standardized assessments. Genetic data obtained analyzed from nine children adolescents between ages 5–17 FOXP1. Phenotypic characterization included gold standard ASD testing norm-referenced measures cognition, adaptive behavior, language, motor, visual-motor integration skills. In addition, psychiatric, medical, neurological, dysmorphology examinations were completed by multidisciplinary team clinicians. A comprehensive review reported cases also performed. All missense in-frame mapped onto three-dimensional structure DNA-bound We identified de novo mutations, including three frameshift, one nonsense, mutation an essential splice site resulting frameshift insertion premature stop codon, missense, deletion. Reviewing prior literature, we found seven instances recurrent another 34 private mutations. majority pathogenic all four our cohort, lie DNA-binding domain. Through structural analyses, show that perturb amino acids necessary for binding DNA or interfere domain swapping mediates dimerization. Individuals syndrome presented delays early motor milestones, impairment (expressive > receptive language), symptoms, deficits, complex presentations characterized anxiety, obsessive-compulsive attention externalizing symptoms. Medical features non-specific brain abnormalities dysmorphic features, endocrine gastrointestinal problems, sleep disturbances, sinopulmonary infections. identifies novel associated demonstrates significant clustering Clinical findings confirm role plays development across domains functioning. can be incorporated into genetics practice improve accurate diagnosis inform monitoring treatment