*Notes prepared by Eric Larsen, Marcel Estevez, Ishita Das, Anjali Sarkar, Andrey Verendeev, Ravi Kollu, and Sharmila Banerjee-Basu of MindSpec, Inc., and edited by Alan Packer of SFARI.
Human Gene module
A total of 17 new genes were added to the Human Gene module, bringing the total number to 1036. In depth annotation of 379 rare variants and 10 common variants was also completed, and 105 new references were added. Noteworthy genes added include:
Parras et al., 2018 reported that CPEB4 bound to the transcripts of a number of high-confidence ASD risk genes, including AUTS2, DYRK1A, and CUL3. In addition, the brains of idiopathic ASD cases showed imbalances in CPEB4 transcript isoforms that resulted from decreased inclusion of a neuron-specific microexon and reduced poly(A) tail length in 9% of the transcriptome. This percentage was much higher for high-confidence ASD risk genes.
Read more here: CPEB4
Three rare de novo variants in MYH10 were identified in ASD probands from the Simons Simplex Collection (Willsey et al., 2013; Iossifov et al., 2014). Hluschchenko et al., 2018 showed that functional analysis of the ASD-associated pTyr265Cys variant in transfected primary rat hippocampal neurons affects the size and density of inhibitory synapses.
Read more here: MYH10
Gene Scoring module
A total of 70 gene scores were added or updated, including 17 newly annotated genes. Additionally, 3 previously scored genes were moved to a higher category based on recent publications. Another set of 12 genes were updated with new evidence but did not merit a higher score. Genes with updated scores include DNMT3A, GRIK4, and IRF2BPL.
Copy Number Variant (CNV) module
A total of 11 newly curated references and 26 novel CNV loci were added to the CNV module, resulting in a total of 583 curated references and 2,276 CNV loci.
Animal Models module
The mouse model dataset was updated with 56 new ASD models, including 23 new rescue models, as well as updated annotations on 11 existing models. Models of noteworthy genes include Chd8, Foxp1, Adnp, and Rims1.
Mouse model annotation highlights include:
Two papers reporting conditional and humanized mutations of Chd8 were annotated this quarter. Zhao and colleagues report the selective ablation of Chd8 in oligodendrocyte progenitors but not neurons, leads to decreased myelination, decreased oligodendrocyte differentiation, decreased post-injury remyelination, increased clasping reflex and tremors, decreased cell proliferation and increased apoptosis. Rescue attempts involving the inhibition of histone deacetylase activity ameliorates defects in myelination in Chd8 knockout mutants (Zhao C., et al., Cell, 2018). In another paper annotated this quarter, male mice bearing the humanized mutation Chd8^+/N2373K show enhanced isolation-induced ultrasonic vocalization, enhanced attachment to reunited mothers, and increase in isolation-induced self-grooming, whereas the female Chd8^+/N2373K mice do not. Female mutant mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix (Jung H, Nat. Neuro., 2018).
See CHD8 mouse model
Hacohen-Kleiman and colleagues (J. Clin. Invest, 2018) report an analysis of a number of sexually dimorphic phenothypes in Adnp mutant mice.
See ADNP mouse model
Rat model annotation highlights include:
Cacna1c heterozygote rats had previously been tested and shown deficits in social behavior and
communications. This newly annotated study indicated that Cacna1c heterozygotes show sexually dimorphic memory phenotypes. Specifically, male Cacna1c heterozygotes show a decrease in cognitive flexibility and female Cacna1c heterozygotes show an increase in working memory, as well as decrease ambulatory activity (Braun et al., 2018)
See CACNA1C rat model
A Shank2 knockout model, where the PDZ domain exon 31 was deleted, showed social behavior deficits, namely in juvenile play, social interaction and social habituation. This model also showed increased ambulatory activity, increased rearing behavior and increased circling behavior. The Shank2 knockout also showed increased motivational behavior and decreased associative learning. Different neurophysiological phenotypes were seen in the hippocampus versus the striatum of knockouts. In the striatum, knockouts had higher levels of mGluR1, increased neuronal soma size and increased dendritic branching. Whereas in the hippocampus, knockouts showed decreased neuronal soma size, and decreased dendritic branching. The hippocampus of Shank2 knockouts had decreased long-term potentiation and long-term depression, whereas the striatum showed increased long-term depression. The Shank2 knockout social and repetitive behavior phenotypes were ameliorated with both a dopamine D1 receptor antagonist and with an mGluR1 receptor antagonist (Modi et al., 2018).
See SHANK2 rat model