*Notes prepared by Eric Larsen, Senanu Spring-Pearson, Anjali Sarkar, Girish Nagendara, and Sharmila Banerjee-Basu of MindSpec, Inc., and edited by Alan Packer of SFARI.
Human Gene module
A total of 30 new genes were added to the Human Gene module, bringing the total number to 1171. In depth annotation of 641 rare variants and 1331 common variants was also completed, and 74 new references were added. Noteworthy genes added include:
- Satterstrom et al. (Cell 180, 1-17 (2020)) reported the largest combined analyses of exome sequences of individuals ascertained specifically for an ASD diagnosis and reported 102 genes passing a false discovery rate of 0.1. Of these genes, 24 are newly added to SFARI Gene, including AP2S1, MAP1A, MKX, SRPRA, GFAP, GNAI1, KIAA0232, LDB1, PHF12, SATB1, SKI, TM9SF4, VEZF1, ZMYND8, CORO1A, GABRB2, LRRC4C, NCOA1, NUP155, PPP1R9B, PPP5C, TEK, TRIM23, and UBR1.
- New syndromic forms of autism are associated with the genes ZMIZ1, TET3, SUPT16H, YWHAG, SRPRA.
Gene Scoring module
Criteria for genes in category 1 have been revised to include both genes on the SPARK list and genes that pass the false discovery rate of 0.1 in the new paper by Satterstrom et al. Cell 180, 1-17 (2020).
Copy Number Variant (CNV) module
A total of 8 newly curated references and 292 individual case records were added to the CNV module, resulting in a total of 619 curated references.
Animal Models module
The mouse module was updated with data from a total of 10 references. Mouse models derived from notable risk genes included Cntnap2, Pten, Fmr1, Cul3, Pogz, Scn1a, MeCP2, and Shank3
Mouse model annotation highlights include:
- CUL3
Dong et al. (Neuron 105, 475-490 (2020)) generated NEX-Cre and GFAP-Cre conditional Cul3-deficient mice, which show social deficits, increased anxiety, enhanced glutamatergic transmission and neuronal excitability. Pharmacological inhibition of eIF4G1, a target of Cul3, and chemogenetic inhibition of neuronal activity of ventral hippocampal pyramidal neurons rescued ASD-associated cellular and behavioral deficits in Cul3 conditional knockout mice. - EIF4G1
EIF4G1 microexon-deficient mice (Gonatopoulos-Pournatzis et al. Mol. Cell 77, 1176-1192 (2020) display deficits in social approach and social memory in the three-chamber assay, decreased social interaction in the reciprocal interaction test, impaired episodic memory measured by the fear conditioning test, and altered hippocampal synaptic plasticity as measured by LTP. They also show increased expression of critical synaptic proteins including GluN1. - POGZ
Mice with Pogz knockdown (Matsumara et al. Nat. Commun. 11, 859 (2020) show impaired cortical neuronal development, impaired neuronal migration and differentiation, increased neuronal excitability, and impaired mature cortical network function. Compensatory inhibition of increased neuronal excitability in Pogz mutants using the anti-epileptic agent perampanel restores sociability in mice carrying a heterozygous mutations at Q1038R.
