The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects

Abstract

Background: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood.

Methods: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools.

Results: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain.

Conclusion: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

Keywords: Autism; Behavior; Epilepsy; Genetic diseases; Intellectual disability; Pierpont syndrome; TBL1XR1.

Fig. 1

Genetic variants reported by survey participants (N = 41). A Types of genetic variants reported in patients diagnosed with Pierpont Syndrome (n = 18) compared to those without a Pierpont diagnosis (n = 23). Genetic information was not provided for 9 subjects. B Location of missense variants (red) and in-frame deletions (blue) in the TBL1XR1 gene reported by survey participants. Recurrent sites are denoted by increased size of the “lollipop” circle. All missense variants (n = 20) and in-frame deletions (n = 3) reported by survey participants occurred in WD40 repeat regions

Fig. 2

Developmental trajectory in patients with TBL1XR1-related disorder.. The age of reported developmental milestone acquisition is shown as a range with a vertical bar denoting the median

Fig. 3

Acquisition of gross motor skills in patients with TBL1XR1-related disorder. Cumulative incidence curves are shown representing the age of acquisition of major motor milestones, with red lines denoting 95% confidence intervals. Respondents were excluded if the skill was attained but the age of acquisition was not reported or if it was unable to be determined whether the skill was obtained

Fig. 4

Gain and loss of language skills in patients with TBL1XR1-related disorder. Cumulative incidence curves are shown representing the age of acquisition and loss of major language milestones, with red lines denoting 95% confidence intervals. Respondents were excluded if the skill was attained or regression occurred but the age of acquisition or regression was not reported. Respondents were also excluded if it was unable to be determined whether the skill was obtained or whether regression occurred

Fig. 5

The presence of seizures and association with developmental regression in patients with TBL1XR1-related disorder. A Cumulative incidence curve is shown representing the onset of seizures in 13 patients by age, with red lines denoting the 95% confidence interval. Respondents were excluded if age at the onset of seizures was not reported. B The presence of regression is shown by developmental domain, with those reporting no regression indicated by ‘none’. Groups are further divided by the presence or absence of seizures