De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Abstract

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.

Fig. 1. Brain MRIs of individuals 1, 19 and 23 compared with MRIs of noncarrier TBR1 variants.

Brain MRIs of individuals with TBR1 variants affecting function in comparison with MRIs of noncarrier individuals (a–d) showing: g, o anomalies of the anterior commissure (AC) (black arrowheads); h, p hippocampal anomalies (white arrowheads); j, k, n cortical gyral anomalies (white arrows and black stars). LR18-042 = individual 1; LR15-186 = individual 23; LR18–210 = individual 19.

Fig. 2. Schematic representation of TBR1 transcript (NM_006593.2) and TBR1 protein with localization of the different SNVs newly reported in this study on the top, and previously reported in the literature below.

The protein contains a DNA-binding motif or T-box domain: amino acids 206–393 (dark blue box), a dimerization domain or T-box associated domain: amino acids 418–680 (dark blue box), a CASK interacting domain: amino acids 342–681 (light blue box), and a FOXP2 interacting domain: amino acids 213–393 (light blue box).

Fig. 3

Schematic representation of the two CNVs discussed in this study, the newly reported CNV of individual 25, and that previously reported by Palumbo et al. [20].

Fig. 4. Neocortical dyslamination and hippocampal dysgenesis in Tbr1 mutant mice (sagittal sections, P14).

a–c Nissl stains of frontal cortex. The cortex was thin and disorganized in TBR1 null cortex (c) compared with wild-type (a) and heterozygous (b) mice. d–f Immunofluorescence for CUX1 (green; upper layers) and CTIP2 (red; deep layers). Compared with wild-type (d) and heterozygous (e) mice, TBR1 null mice (f) showed thin and disorganized cortical layers, with a “mirror-image” laminar phenotype consisting of deep layers sandwiched between upper layers. g, i, k Nissl stains of hippocampus. In TBR1 null mice (k), the pyramidal layer of CA3 was less compact, and the dentate gyrus (DG) was much smaller than in wild-type (g) and heterozygous (i) mice. h, j, l Immunofluorescence for TBR2 (green), a marker of neurogenic intermediate progenitors (IPs; Hodge et al. [33, 34], revealed an immature pattern in TBR1 heterozygous and homozygous mutants. In wild-type mice, TBR2 + IPs were restricted almost exclusively to the subgranular zone (SGZ) of the DG (arrowheads, h). In TBR1 heterozygotes, IPs were dispersed outside the SGZ, notably in the hilus (Hi) of the DG (arrowhead, j). In TBR1 null mice (l), many IPs were clustered at the fimbriodentate junction, a transient niche normally regressed by P14, while other IPs were dispersed in the SGZ, Hi, and molecular layer (Mol; arrowhead, l) of the DG. Scale bar = 100 µm. m–o Immunofluorescence detection of Reelin (green) and Prox1 (red) in dentate gyrus. Reelin expression was markedly reduced in TBR1 null dentate gyrus and neocortex (not shown). Orientation: rostral left, dorsal up. Orientation: sagittal sections, rostral left, dorsal up. Scale bars (a, d, h) = 100 µm; scale bar (o) = 250 µm. hf hippocampal fissure.