Prospective investigation of FOXP1 syndrome

Abstract

BackgroundHaploinsufficiency 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 was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments.MethodsGenetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5–17 with mutations in FOXP1. 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.ResultsWe have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. 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.ConclusionsThis 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 development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.Electronic supplementary materialThe online ver...

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

“…Reinforcing this hypothesis, previous reports have associated brain transcripts levels alterations on this TF in patients diagnosed with BD, schizophrenia and other mood‐related disorders (Ben‐Shachar & Karry, ; Pinacho et al., ; Shi et al., ; Shyn et al., ; Tam et al., ). Analyzing FOXP1 (variants associated with obesity could disturb the binding site of this TF) has been previously associated with speech development, and deleterious genetic variants are known to cause FOXP1 syndrome (Siper et al., ); patients with this syndrome have psychiatric alterations and almost 30% of them are obese (Le Fevre et al., ; Lloveras et al., ), suggesting a possible link between FOXP1 and obesity. FOXP1 is a TF critical in the fate of adult striatum medium spiny neurons projection and its transcript is highly up‐regulated in the whole ganglionic eminence (Precious et al., ).…”

“…). Analyzing FOXP1 (variants associated with obesity could disturb the binding site of this TF) has been previously associated with speech development, and deleterious genetic variants are known to cause FOXP1 syndrome(Siper et al, 2017); patients with this syndrome have psychiatric alterations and almost 30% of them are obese (LeFevre et al, 2013;Lloveras et al, 2014), suggesting a possible link between FOXP1 and obesity. FOXP1 is a TF critical in the fate of adult striatum medium spiny neurons projection and its transcript is highly up-regulated in the whole ganglionic eminence…”

Genomic Influences on Self-Reported Childhood Maltreatment

“…Notably, variation within FOXP1 has been found to have associations with language impairment, internalizing symptoms, and externalizing symptoms 41 . FOXP2 has mainly been investigated in regards to speech and language development 42 , but has also been found to be associated with depression 43 and attention deficit hyperactivity disorder (ADHD) 44 .…”

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy

“…Through a targeted analysis pipeline, we identified variants within the 3′ UTR of the FOXP1 gene at c.3413_3414 in both the proband and his unaffected father. Previously, variants within the functional domains of the FOXP1 protein have been associated with autism (Carr et al, ; Hamdan et al, ; Horn, ); Pariani, Spencer, Graham, & Rimoin, ) and more recently, FOXP1 related ID syndrome (Meerschaut et al, ; Siper et al, ). For this reason, we identified FOXP1 as a possible causative variant in this case.…”