title: A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.
abstract: FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency.
authors: Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA.
authors: Reymundo
authors: R
authors: Lozano
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
authors: Arianna
authors: A
authors: Vino
authors: Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA.
authors: Cristina
authors: C
authors: Lozano
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors: Simon E
authors: SE
authors: Fisher
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
authors: Pelagia
authors: P
authors: Deriziotis
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007806:Language Disorders / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D021381:Protein Transport; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins