*Notes prepared by Eric Larsen, Senanu Spring-Pearson, Marcel Estevez, Ishita Das, Anjali Sarkar, Ravi Kollu, Girish Nagendara 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 1053. In depth annotation of 583 rare variants and 16 common variants was also completed, and 120 new references were added. Noteworthy genes added include:
Wang et al., 2018 reported a rare de novo nonsense variant and inherited damaging missense variants in Han Chinese ASD probands. PAK2 resides in the 1.5-Mb region on chromosome 3q29, which underlies the 3q29 microdeletion syndrome associated with autism and schizophrenia.
Read more here: PAK2
Kishima et al., 2018 reported a significant enrichment of exonic CNVs affecting CDH13 in a combined Japanese cohort of ASD and schizophrenia cases compared to controls. A de novo missense variant in CDH13, encoding cadherin 13, was previously reported in a proband from the Simons Simplex Collection.
Read more here: https://gene.sfari.org/database/human-gene/CDH13
Gene Scoring module
A total of 53 gene scores were added or updated, including 17 newly annotated genes. Additionally, 7 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 AGO1, CEP290, CNOT3, GLRA2, ICA1, NBEA, and NCOR1.
Copy Number Variant (CNV) module
A total of 14 newly curated references and 11 novel CNV loci were added to the CNV module, resulting in a total of 597 curated references and 2,285 CNV loci.
Animal Models module
The mouse model dataset was updated with 55 new ASD models, including 26 new rescue models, as well as updated annotations on 8 existing models. Models of noteworthy genes include Pak2, Setd5, Mir137, Shank2, and Syngap1.
Mouse model annotation highlights include:
Deliu and colleagues (Nat. Neuro., 2018), reported that Setd5 heterozygous mice show abnormal brain-to-body weight ratio, neural crest abnormalities, increased LTP, delayed ultrasonic vocalizations, reduced cognitive flexibility, deficits in nest building behavior, and abnormalities in the regulation of transcription.
See Setd5 mouse model
Cheng and colleagues (Nat. Neuro., 2018) reported mice with homozygous germline deficiency of the microRNA miR-137, or conditional knockout in neurons. These mice show postnatal lethality with decreased body and brain size, while heterozygous mice show deficits in synaptic plasticity, repetitive behavior, learning, impaired social interaction, and elevated levels of the phosphodiesterase PDE10a. Treatment with the PDE10a inhibitor papaverine rescues social behavior, repetitive digging, and memory deficits in the miR-137 heterozygotes.
See Mir137 mouse model
Rat model annotation highlights include:
Auditory processing is altered in individuals with ASD. CNTNAP2 is associated with language-processing deficits. Scott and colleagues (J. Neurosci., 2018) report an assessment of auditory processing in the Cntnap2 knockout rat model. Although the knockout rats do not exhibit a change in hearing threshold, they do show an increase in the startle response to an auditory stimulus, as well as a decrease in paired-pulse inhibition. In the auditory brain response, Cntnap2 knockouts showed a decrease in amplitude of wave IV of the response, and an increase in latency between waves. Knockout rats also showed decreased habituation to auditory stimuli and an increase in response to a novel environment.