*Notes prepared by Eric Larsen, Marcel Estevez, Ishita Das, Anjali Sarkar, Wayne Pereanu, Ravi
Kollu, and Sharmila Banerjee-Basu of MindSpec, Inc., and edited by Alan Packer of SFARI.
Human Gene module
A total of 20 new genes were added to the Human Gene module, bringing the total number to
990. In depth annotation of 570 rare variants and 18 common variants was also completed, and
80 new references were added. Noteworthy genes added include:
- CHD1
A new study described six individuals with a neurodevelopmental disorder carrying
heterozygous missense variants in CHD1, building on the previous evidence of de novo
mutations in this gene. Two of the individuals were diagnosed with ASD. Other
chromodomain helicase proteins, including CHD2, CHD7, and CHD8 have already been
associated with ASD.
Read more here: CHD1 - RAC1
De novo missense variants in RAC1 were identified in seven individuals with intellectual
disability and brain malformations, with one being diagnosed with autism. Previous work in
mice links RAC1 to social behavior.
Read more here: RAC1 - EBF3
A new report identified seven individuals with de novo mutations in EBF3, two of whom had
a diagnosis of autism and another two were described as having autistic features. Previously
EBF3 has been linked to developmental delay.
Read more here: EBF3
Gene Scoring module
A total of 74 gene scores were added, including 20 newly annotated genes. Additionally, seven
previously scored genes were moved to a higher category based on recent publications.
Another set of four genes were updated with new evidence but did not merit a higher score.
Genes with updated scores include CAMK2A, IMMP2L, KMT2C, PHIP, TCF4, TRIO, and USP15.
Copy Number Variant (CNV) module
A total of 13 newly curated references and 7 novel CNV loci were added to the CNV module,
resulting in a total of 556 curated references and 2,225 CNV loci.
New references provided additional support for CTCF, EBF3, and NFIX as ASD risk genes.
Read more here: 16q22.1
Read more here: 10q26.3
Read more here: 19p13
Animal Models module
The mouse model dataset was updated with five new genes, including Plppr4, Kctd13, Rims1,
Upf3b, and Rheb. Additionally, many mouse models based on high-confidence genes were
added, including MeCP2 and Fmr1. Forty new rescue models were also added, and all told a
total of 70 new models were annotated this quarter.
Mouse model annotation highlights include:
A new model of MeCP2 shows that it binds to the NCoR/SMRT complex to methylate sites on
chromatin, and that the NCoR/SMRT interaction domain is the critical region of the protein.
(Tillotson et al., 2017)
See MeCP2 in Mus musculus
A new model of Fmr1 includes immune response-related phenoterms. While the majority of
ASD mouse models mimic the heightened pro-inflammatory cytokine expression seen in some
individuals with ASD, this Fmr1 mouse shows a decrease in pro-inflammatory cytokines.
(Hodges et al., 2017)
See FMR1 in Mus musculus
Kctd13 is in the 16p11.2 CNV interval, and new mouse models identify a role for Kctd13 in
reducing excitatory synaptic transmission in a RhoA-dependent manner.
(Escamilla et al., 2017)
See KCTD13 in Mus musculus
The rat model dataset has been updated with eight new models and new data for three existing
models. The dataset includes four new ASD models from existing environmental inducers
(lipopolysaccharide, terbutaline, and valproic acid).
Rat model annotation highlights include:
The rat Nlgn3 knockout exhibits increased activity and stereotypical behavior but no impaired
social behavior. This model also shows abnormal sleep patterns.
(Thomas et al., 2017)
See NLGN3 in Rattus norvegicus
In vivo recordings of a Shank3 knockout show that this model has a decreased baseline of
action potential firing and an abnormal rate of action potential membrane depolarization. The
sensory-evoked response to an auditory stimulus is also reduced
(Engineer et al., 2017)
See SHANK3 in Rattus norvegicus
