Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms

M Pilar Trelles, Tess Levy, Bonnie Lerman, Paige Siper, Reymundo Lozano, Danielle Halpern, Hannah Walker, Jessica Zweifach, Yitzchak Frank, Jennifer Foss-Feig, Alexander Kolevzon, Joseph Buxbaum, M Pilar Trelles, Tess Levy, Bonnie Lerman, Paige Siper, Reymundo Lozano, Danielle Halpern, Hannah Walker, Jessica Zweifach, Yitzchak Frank, Jennifer Foss-Feig, Alexander Kolevzon, Joseph Buxbaum

Abstract

Background: FOXP1 syndrome is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, speech and language delays, and externalizing behaviors. We previously evaluated nine children and adolescents with FOXP1 syndrome to better characterize its phenotype. We identified specific areas of interest to be further explored, namely autism spectrum disorder (ASD) and internalizing and externalizing behaviors.

Methods: Here, we assess a prospective cohort of additional 17 individuals to expand our initial analyses and focus on these areas of interest. An interdisciplinary group of clinicians evaluated neurodevelopmental, behavioral, and medical features in participants. We report results from this cohort both alone, and in combination with the previous cohort, where possible.

Results: Previous observations of intellectual disability, motor delays, and language deficits were confirmed. In addition, 24% of the cohort met criteria for ASD. Seventy-five percent of individuals met DSM-5 criteria for attention-deficit/hyperactivity disorder and 38% for an anxiety disorder. Repetitive behaviors were almost universally present (95%) even without a diagnosis of ASD. Sensory symptoms, in particular sensory seeking, were common.

Limitations: As FOXP1 syndrome is a rare disorder, sample size is limited.

Conclusions: These findings have important implications for the treatment and care of individuals with FOXP1 syndrome. Notably, standardized testing for ASD showed high sensitivity, but low specificity, when compared to expert consensus diagnosis. Furthermore, many individuals in our cohort who received diagnoses of attention-deficit/hyperactivity disorder or anxiety disorder were not being treated for these symptoms; therefore, our findings suggest that there may be immediate areas for improvements in treatment for some individuals.

Keywords: Anxiety; Attention-deficit/hyperactivity disorder; Autism spectrum disorder; FOXP1 gene; FOXP1 syndrome; Intellectual disability; Neurodevelopment.

Conflict of interest statement

A. Kolevzon receives research support from AMO Pharma and consults to Ovid Therapeutics, Acadia, Alkermes, Sema4, and Ritrova. PMS and Mount Sinai licensed the Sensory Assessment for Neurodevelopmental Disorders (SAND) developed by PMS to Stoelting, Co. No other competing interests to declare.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Assessment and methods. a Genetic landscape. b Assessment battery
Fig. 2
Fig. 2
Intellectual and adaptive functioning. Intellectual quotient (IQ; n = 22) and adaptive function scores (Vineland-3; n = 16) are presented as standard scores, illustrating the distribution of scores as it compares to the general population
Fig. 3
Fig. 3
Language functioning. a Vineland Communication standard scores and subscale V scores (n = 16). b Receptive and expressive language are presented for comparison (n = 19). c PPVT and EVT standard scores presented for each participant. Two participants, with PPVT receptive standard score of 20, and who could not complete the EVT were excluded from figures
Fig. 4
Fig. 4
ASD symptomatology. a Z-normalized scores for each participant ordered by severity of ADOS-2 comparison scores from less severe to more severe. Each row represents a participant. Results show that despite a tendency toward more severe scores on instruments used to assess ASD for individuals with a DSM-5 ASD diagnosis, there is large variability in the neurobehavioral profile of individuals with FOXP1 syndrome. b Average SRS T-scores are presented comparing FOXP1 participants with and without ASD (bars represent standard deviation). c Sensory symptoms as assessed by the SAND are presented against a typically developing population and an ASD normed population
Fig. 5
Fig. 5
Behavioral and psychiatric profile. a. Participants who received ADHD and anxiety diagnoses, and those with a history of aggressive behavior are presented as a proportion of the cohort. b CBCL T-scores are presented against psychiatric diagnoses and/or behavioral concerns for each participant. Each row represents a participant. Scores were ranked by CBCL attention scores. CBCL attention and ADHD correlate with the presence of an ADHD diagnosis, but the same is not observed for the other CBCL subscales. * Denotes participants on psychotropic medications for the specified diagnosis. c BRIEF T-score subscales of FOXP1 participants (n = 17) presented against normed samples for ASD, ADHD-combined type, and individuals with typical development
Fig. 6
Fig. 6
Pictures of participants

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