*Notes prepared by Eric Larsen, Marcel Estevez, Ishita Das, Anjali Sarkar, Andrey Verendeev, Girish Nagendra Padaval, Ravi Kollu, and Sharmila Banerjee-Basu of MindSpec, Inc., and edited by Alan Packer of SFARI.
Human Gene module
A total of 12 new genes were added to the Human Gene module, bringing the total number to 1019. In depth annotation of 291 rare variants and 4 common variants was also completed, and 101 new references were added. Noteworthy genes added include:
In a recent whole-genome sequencing study, paternally inherited deletions of the LEO1 promoter were preferentially transmitted to affected offspring and not to unaffected siblings. These deletions led to increased LEO1 expression in fibroblast cell lines.
Read more here: LEO1
A modified version of Transmission and De Novo Association (TADA) analysis was used to consider the functional relevance of non-coding variants in ASD risk, implicating several genes, including APBB1.
Read more here: APBB1
Gene Scoring module
A total of 30 gene scores were added, including 12 newly annotated genes. Additionally, 8 previously scored genes were moved to a higher category based on recent publications. Another set of 7 genes were updated with new evidence but did not merit a higher score. Genes with updated scores include BTAF1, MED13, NAA15, PPM1D, RAI1, RORA, TANC2, and TLK2. One gene (CUX1) was updated from category 3 to 2 based on a new gene scoring criterion that takes account of recurrent non-coding genetic variants identified in ASD probands (see category 2.4 and 3.4).
Copy Number Variant (CNV) module
A total of 9 newly curated references and 8 novel CNV loci were added to the CNV module, resulting in a total of 572 curated references and 2,250 CNV loci.
New references provided additional support for KANK1 and NR4A2 as ASD risk genes.
Read more here: https://gene.sfari.org/database/cnv/9p24.3
Read more here: https://gene.sfari.org/database/cnv/2q24.1
Animal Models module
The mouse model dataset was updated with 27 new ASD models and 32 new rescue models, as well as updated annotations on 10 existing models. Models of noteworthy genes and CNVs include Chd8, Shank3, Nlgn3, Cntnap2, and 16p11.2.
Mouse model annotation highlights include:
A new model of Chd8 mutation shows increased brain size, motor delay, hypertelorism, hypoactivity, and deficits in social behavior. Chd8 heterozygous mice show aberrant gene expression in the neocortex at mid-gestation and in the early postnatal period, as well as increased functional synchronization in the cortico-hippocampal and auditory-parietal networks (Suetterlin et al., 2018).
Treatment of Shank3-deficient mice with romidepsin or knockdown of HDAC2 in the prefrontal cortex alleviates social deficits. Shank3-deficient mice show upregulation of HDAC2 transcription and an increase in nuclear localization of beta-catenin (Qin et al., 2018).
Stxbp1 heterozygous mice with different genomic backgrounds recapitulate the seizure/spasm phenotype observed in humans, which were rescued by the anti-epileptic drug levetiracetam. Conditional heterozygotes with selective Stxbp1 deficiency in GABAergic neurons showed increased early postnatal mortality and seizures (Kovacevic et al., 2018).
Rat model annotation highlights include:
The rat Cacna1c shows decreased emission of prosocial ultrasonic vocalizations during juvenile play, as well as decreased social approach in a radial maze paradigm.
(Kisko et al., 2018)
Vitamin D-deficient rats show phenotypes in ASD core categories, including communications, social behavior and repetitive behavior. Specifically, pups with developmental vitamin D deficiency show increased ultrasonic vocalizations in response to maternal separation, accompanied by decreased Foxp2 expression in the cortex (Yates et al., 2018).
See Vitamin D-deficiency