*Notes prepared by Eric Larsen, Marcel Estevez, Ishita Das, Anjali Sarkar, Girish Nagendra, 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
1,007. In depth annotation of 522 rare variants and 39 common variants was also completed, and
112 new references were added. Noteworthy genes added include:
A new study of 262 Japanese trios with ASD, combined with previous evidence for GGNBP2, identifies the gene as being significantly enriched for damaging de novo mutations.
Read more here: GGNBP2
A new study of 262 Japanese trios with ASD, combined with previous evidence for DPYSL2, identifies this gene as being significantly enriched for damaging de novo mutations. DPYSL2 has also been associated with increased risk of schizophrenia.
Read more here: DPYSL2
A new study identifies OTUD7A, which localizes to dendritic and spine compartments in cortical neurons, as a key driver of the phenotypes associated with the 15q13.3 microdeletion syndrome.
Read more here: OTUD7A
Gene Scoring module
A total of 118 gene scores were added, including 17 newly annotated genes. Additionally, nine previously scored genes were moved to a higher category based on recent publications. Another set of 11 genes were updated with new evidence but did not merit a higher score. Genes with updated scores include ATP1A3, CHD2, FRMPD4, MED13L, MTOR, PHIP, SLC6A1, TSC2, and TTN.
Copy Number Variant (CNV) module
A total of 7 newly curated references and 17 novel CNV loci were added to the CNV module, resulting in a total of 563 curated references and 2,242 CNV loci.
Animal Models module
The mouse model dataset was updated with 29 new models, including Ahrgef10, Ambra1, Dagla, Dlgap1, Kirrel3, Otud7a, Slc9a9, and Taok2. Additionally, many mouse models based on high-confidence genes were added, including Cacna1c, Met, and Shank3. Eleven new rescue models were also added.
Mouse model annotation highlights include:
Ambra1 heterozygous mutant mice show female specific deficits in social interaction, decreased ultrasound communication in adults and pups, increased tendency for repetitive behaviors, and reduced cognitive flexibility. Sexual dimorphism of the Ambra1 heterozygous phenotype is partly explained by a strong reduction in Ambra1 protein in the cerebral cortex of females but not males (Dere et al., 2014).
Slc9a9-deficient mice exhibit impaired social interaction, repetitive behaviors, and altered sensory processing. In addition, they show hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression, and impaired neurotransmitter release due to a defect in presynaptic calcium entry (Ullman et al., 2018).
Kirrel3-null mice display preference for a mouse over a non-social object but not significant preference for a stranger mouse over a familiar mouse. These mice also show impaired ultrasonic communications, increased locomotor activity and repetitive rearing, as well as enhanced performance on the rotarod and hypersensitivity to acoustic stimuli.
The rat model dataset has been updated with 17 new models and new data for 4 existing models. The dataset includes 7 new ASD models from existing environmental inducers (isolation, poly I:C, and valproic acid).
Rat model annotation highlights include:
Shank3 knockout rats were tested in a novel radial maze test with a pro-social USV playback. All rats were responsive; however, Shank3 null male rats showed decreased exploration of the proximal arm to the playback, once the playback stopped. This novel method of quantifying social approach produced a different result than the traditional three-chamber sociability test, where the same rets exhibited normal sociability (Berg et al., 2018).
A Pcdh19 knockdown model shows that this gene is important for pyramidal neuron lamination in the hippocampus, and for maintaining dendritic length for these neurons. Overexpressing human PCDH19 alongside the knockdown restores all associated phenotypes. Furthermore knockdown of Pcdh19, which is linked to female epilepsy, results in higher susceptibility to chemically-induced seizures (Bassani et al., 2018).