To the Editor:
We thank Hsueh et al. for their interest in our article, and for their comments emphasizing the significance of anterior commissure (AC) hypoplasia/agenesis as a common feature in TBR1 deficient mice and humans. We agree that our statement about AC defects not having been previously reported in mice or humans with TBR1 alterations was mistaken, and we regret this inadvertent oversight. In fact, our main goal was to draw attention to the novel hippocampal dysgenesis that we observed in TBR1 deficient mice and humans , which could impact learning and memory.
Severe defects of the AC (anterior and posterior limbs) were originally reported 19 years ago in homozygous Tbr1−/− mice . More recently, the Hsueh group made important novel contributions showing that heterozygous Tbr1+/− mice also had AC defects, primarily agenesis/hypoplasia of the posterior limb of the AC , along with subtle hypoplasia of the anterior AC . Thus, AC defects are shared among heterozygous [3, 4] and homozygous  Tbr1 mutant mice, as well as humans with heterozygous TBR1 mutations/haploinsufficiency .
The hypothesis that abnormal connections of the amygdala, including deficient posterior AC connections, may contribute to autism-related behavioral problems in TBR1 deficient mice and humans  is interesting. On the other hand, the neocortical and hippocampal dysgenesis documented in many TBR1 patients  indicates that TBR1 deficiency has widespread effects on cortical as well as amygdala development. We fully agree that novel therapeutic approaches, such as treatment with D-cycloserine, should be investigated for patients with the TBR1 neurocognitive phenotype.
Nambot S, Faivre L, Mirzaa G, Thevenon J, Bruel A-L, Mosca-Boidron A-L, et al. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature. Eur J Hum Genet. 2020. https://doi.org/10.1038/s41431-020-0571-6.
Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S, et al. Tbr1 regulates differentiation of the preplate and layer 6. Neuron. 2001;29:353–66.
Huang TN, Chuang HC, Chou WH, Chen CY, Wang HF, Chou SJ, et al. Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nat Neurosci. 2014;17:240–7.
Huang TN, Yen TL, Qiu LR, Chuang HC, Lerch JP, Hsueh YP. Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice. Mol Autism. 2019;10:5.
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Nambot, S., Hevner, R.F. & Dobyns, W.B. Reply to Hsueh YP et al.. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-0622-z