*Notes prepared by Eric Larsen, Senanu Spring-Pearson, Marcel Estevez, Ishita Das, Anjali Sarkar, Girish Nagendara, Ravi Kollu and Sharmila Banerjee-Basu of MindSpec, Inc., and edited by Alan Packer of SFARI.
Human Gene module
A total of 26 new genes were added to the Human Gene module, bringing the total number to 1079. In depth annotation of 700 rare variants and 9 common variants was also completed, and 63 new references were added. Noteworthy genes added include:
An integrated meta-analysis of de novo mutation data from individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (Coe et al., 2018). In addition, Cogne et al. (2019) reported 24 individuals with de novo mutations in TRRAP, some of which were diagnosed with ASD.
Read more here: TRRAP
An integrated meta-analysis of de novo mutation data from individuals with neurodevelopmental disorders identified WDFY4 as a gene with an excess of missense variants (Coe et al., 2018).
Read more here: WDFY4
Gene Scoring module
A total of 43 gene scores were added or updated, including 26 newly annotated genes. Additionally, 8 previously scored genes were moved to a higher category based on recent publications. Another set of 9 genes were updated with new evidence but did not merit a higher score. Genes with updated scores include CEP41, GRIN2A, MACROD2, NCOR1, NEGR1, SMARCC2, TCF20, and USP7.
Copy Number Variant (CNV) module
A total of 7 newly curated references and 86 individual case records were added to the CNV module, resulting in a total of 604 curated references and 2,286 CNV loci.
Animal Models module
The mouse model dataset was updated with 42 new ASD models, including 21 new rescue models. Models of noteworthy genes include Tbr1, Tcf4, Adnp, Cyfip1, Setd5, and Shank3.
Mouse model annotation highlights include:
Antoine et al. (2019) reported in Neuron on a comparison of excitatory and inhibitory neurotransmission in the cortex of Fmr1, Tsc1, Cntnap2 and 16p11.2del mice. They find decreased feedforward inhibition in layer 2/3 of somatosensory cortex, variable reduction in feedforward excitation and decreased in E:I conductance ratio with no change in synaptic depolarization. The authors suggest that E:I ratio changes may be compensatory in ASD, rather than a causative mechanism.
Moore et al. (2019) reported in Translational Psychiatry that Setd5 heterozygous mice show delayed development of synchronized cortical neuronal networks, abnormal social interaction, increased anxiety, decreased nest-building capacity, and aberrant cortical lamination, among other phenotypes.
See Setd5 mouse model
Rat model annotation highlights include:
A comparative analysis of three rat genetic models (Fmr1, Nrxn1, Pten) used diffusion tensor imaging (DTI) to assess structural changes in brain morphology. All three models showed global changes in DTI parameters of anisotropy and diffusivity, which measure white matter fiber tract morphology (Rowley et al., 2019).