* 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 60 new genes were added to the Human Gene module, bringing the total number to 970. In depth annotation of 1,134 rare variants and 12 common variants was also completed, and 81 new references were added. Noteworthy genes added include:
A homozygous founder splice-site variant in TRAPPC6B was identified in six individuals from three unrelated Egyptian families presenting with a neurodevelopmental disorder characterized by autistic features.
Read more here: TRAPPC6B
Recurrent gain-of-function missense variants (p.Ala636Thr) were reported in GRIA1 in three individuals with a primary diagnosis of ASD, building on previous reports of the same missense variant being found in individuals with developmental delay and/or intellectual disability.
Read more here: GRIA1
Additional evidence supporting SMARCA4 as an ASD risk gene comes from new analyses of non-synonymous postzygotic mutations.
Read more here: SMARCA4
Gene Scoring module
A total of 70 gene scores were added, including 60 newly annotated genes. Additionally, six previously scored genes were moved to a higher category based on recent publications. Another set of three genes were updated with new evidence but did not merit a higher score. Genes with updated scores include CX3CR1, FOXG1, FOXP1, HECTD4, NLGN1, and SMC3.
Copy Number Variant (CNV) module
A total of 12 newly curated references and 21 novel CNV loci were added to the CNV module, resulting in a total of 543 curated references and 2,218 CNV loci.
New references provided additional support for BCL11A, TBL1XR1, and FOXP1 as ASD risk genes, and in the cases of BCL11A and TBL1XR1, as the primary contributors to the phenotype associated with previously reported microdeletion syndromes.
Read more here: 2p16.1
Read more here: 3q26.32
Read more here: 3p13
Animal Models module
The mouse model dataset was updated with six new genes, including Arid1b, Cbln1, Chd5, Eef1a2, Lrfn2, and Pcdh19. Additionally, many mouse models based on high-confidence genes were added, including Chd8, Cntnap2, Fmr1, Nlgn3, and Ptchd1. Fifteen new rescue models were also added, and all told a total of 62 new models were annotated this quarter.
Mouse model annotation highlights include:
Optogenetic restoration of normal excitatory-to-inhibitory balance in the medial prefrontal cortex of Cntnap2-null mice rescues normal social behavior and reduces hyperactivity (Selimbeyoglu et al., 2017)
See Genetic Animal Model: CNTNAP2
Supplementation with growth hormone rescued muscle weakness and growth retardation in Arid1b heterozygous mice (Celen et al. 2017)
See Rescue Model: ARID1B
Chd5 homozygous knockout mice show abnormal social and communicative behavior, and a decreased preference for novelty (Pisansky et al., 2017)
See Genetic Animal Model: CHD5
The rat model dataset has been updated with 13 new models and new data for five existing models. The dataset includes three new ASD models and four existing models from four existing environmental inducers (fluoxetine, lipopolysaccharide, maternal stress, and valproic acid), and three models from two new inducers (BK channel blocker and BK channel opener). Highlights include:
The BK channel is encoded by Kcnma1, a gene associated with ASD. Bidirectional modulation of BK channel function regulates habituation and underlying synaptic plasticity. In a rat model, BK channel blockers have no effect on habituation, whereas a BK channel opener increases habituation to an acoustic stimulus (Zaman et al., 2017)
See BK channel blocker
See BK channel opener
The interaction between fluoxetine and pregestational maternal stress in ASD-relevant behaviors was studied in rats. Fluoxetine increased aggressive behavior and reduced social behavior with novel conspecifics (Gemmel et al., 2017)
A new study of lipopolysaccharide administration in rats shows that it can lead to repetitive or stereotypic behaviors, such as self-grooming.