*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 32 new genes were added to the Human Gene module, bringing the total number to
1220, and 91 new references were added. Noteworthy genes added include:
A de novo missense variant that was predicted to be damaging was identified in CNOT1 in
an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Vissers et al.,
2020 reported on 39 individuals with CNOT1 variants (34 previously unreported cases and
the 5 cases previously described in Kruszka et al., 2019 and De Franco et al., 2019) who
presented with a clinical spectrum of intellectual disability, motor delay, speech delay,
seizures, hypotonia, and behavioral problems. Of the 32 individuals assessed for behavioral
abnormalities, 9 presented with autism spectrum disorder.
A cross-trait met-analysis of genome-wide association studies on schizophrenia (65,967
cases), bipolar disorder (41,653 cases), autism spectrum disorder (46,350 cases), ADHD
(55,374 cases) and depression (688,809 cases) identified an intronic SNP in SORCS3 that
reached genome-wide significance for ASD following MTAG analysis (Wu et al., 2020). Other
SNPs in this gene have previously been shown to reach genome-wide significance for ADHD
(Demontis et al., 2018) and depression (Wray et al., 2018; Howard et al., 2019). A de novo
nonsense variant in SORCS3 was identified in an ASD proband from the Autism Sequencing
Consortium (De Rubeis et al., 2014).
Two rare de novo missense variants in CSNK2A1 have been identified in ASD probands from
simplex families of the Simons Simplex Collection (Iossifov et al., 2014) and the ASD:
Genomes to Outcome Study cohort (Yuen et al., 2017). Heterozygous variants in CSNK2A1
are also responsible for Okur-Chung neurodevelopmental syndrome (OMIM 617062), an
autosomal dominant disorder characterized by delayed psychomotor development,
intellectual disability with poor speech, behavioral abnormalities, cortical malformations in
some patients, and variable dysmorphic facial features. Autistic features and/or stereotypy
have been reported in a subset of affected individuals (Okur et al., 2016; Trinh et al., 2017;
Chiu et al., 2018; Owen et al., 2018; Martinez-Monseny et al., 2020).
Gene Scoring module
For new genes, a score of 2 was assigned to CNOT1, SORCS3, DCC, GALNT10, SCAF4, DDHD2,
FGFR1, and MAPT-AS1. A score of 3 was assigned to PJA1, MSX2, CLIP2, WWP1, FXN, FGF14,
CACNB1, CDON, MYOCD, NXF1, LDLR, MYLK, KNG1, VWA7, NCAPH2, SYCE1, AGAP5, PEBP4,
TNS2, TMEM134, TRAPPC2L, BRINP3, and UNC5D. A score of 3S was assigned to CSNK2A1.
Copy Number Variant (CNV) module
A total of 9 newly curated references and 29 individual case records were added to the CNV
module, resulting in a total of 643 curated references.
Animal Models module
The mouse module was updated with data from a total of 11 references. Mouse model
annotation highlights include:
- Auts2 heterozygous mice show increased dendritic spine formation during development and
adulthood, increased excitatory synaptic transmission frequency but not amplitude, increase in
the number of excitatory synaptic transmission frequency but not amplitude, increase in the
number of excitatory synapses in the forebrain, increase in c-fos expression in the mPFC and
CA1 region, abnormal spine morphology and maturation, and impairments in social interaction
and a range of other ASD-relevant behaviors. Selective inducible ablation of Auts2 in forebrain
pyramidal neurons at P30-P34 resulted in decreased social interaction and ultrasonic
vocalization, while selective inducible ablation of Auts2 in forebrain pyramidal neurons at P21-
P25 showed increased spine density and abnormal spine morphology (Hori et al., 2020).
- Cttnbp2 deficiency reduces zinc levels in the brain, alters synaptic protein targeting, impairs
dendritic spine formation and ultrastructure of postsynaptic density, increases activity levels,
reduces anxiety levels, reduces cognitive flexibility, reduces spatial memory, reduces c-fos
expression, and alters NMDAR expression. Mice with the ASD-linked R533* mutation in Cttnbp2
recapitulated decreased social interaction, decreased ultrasonic vocalization and abnormal
dendritic spine morphology as well as reduced zinc levels in the brain. Zinc supplementation
rescues the synaptic expression of Cttnbp2-regulated proteins and rescues social behavior, and
D-cycloserine improves social behaviors of Cttnbp2-deficient mice (Shih et al., 2020).
- Mice with Tcf20 knockdown in the brain, and heterozygous or null KOs, show reduced number
of neurons due to reduced neuronal cell proliferation, impaired neuronal differentiation,
abnormal brain functions, abnormal DNA methylation and gene expression, reduced ultrasonic
vocalization, increased anxiety, increased repetitive digging, decreased social interaction and
social memory. Overexpression of downstream factors of Tcf20, Tdg or Tcf4, rescues the
deficient neurogenesis of Tcf20 knockdown brains (Feng et al., 2020).