*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 11 new genes were added to the Human Gene module, bringing the total number to 1231, and 54 new references were added. Noteworthy genes added include:
Lessel et al. (2020) identified 21 individuals carrying heterozygous variants in AGO2 that impaired shRNA-mediated silencing. All 21 affected individuals presented with intellectual disability, motor delay, and delayed speech and language development, while 9/16 (56%) had autistic features.
Brunet et al. (2020) delineated the genotypic and phenotypic spectrum of 25 individuals (15 males, 10 females) with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome) and found that 10/20 (50%) individuals had a diagnosis of autism spectrum disorder. De novo likely gene-disruptive (dnLGD) variants in MSL3 were identified in an ASD proband from the SPARK cohort (Wang et al., 2020) and in four probands from the Deciphering Developmental Disorders study in 2017, while a de novo missense variant in MSL3 was identified in a female ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020. MIP-based sequencing of 125 genes in over 16,000 cases with neurodevelopmental disorders in Wang et al. (2020) identified an additional likely gene-disruptive variant in an ASD proband from the AGRE cohort.
MIP-based sequencing of 3,363 probands from cohorts with a primary diagnosis of ASD in Wang et al. (2020) identified 5 ASD-associated LGD variants and one ASD-associated missense variant with a CADD score ? 30 in PHF7. A de novo likely gene-disruptive (LGD) variant in PHF7 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).
Gene Scoring module
For new genes, a score of 2 was assigned to AGO2, AHNAK, PHF7, MYH9, and BICRA. A score of 2S was assigned to ZMYM2 and NSD2. A score of 3 was assigned to KAT6B, FABP4, and CSNK1G1. For previously scored genes, the following genes have a newly assigned score of 1: PAH, SMARCA4, and SYN1, or 1S: CSNK2A1, MEF2C, MSL3, and SETD1A.
Copy Number Variant (CNV) module
A total of 11 newly curated references and 82 individual case records were added to the CNV module, resulting in a total of 654 curated references.
Animal Models module
The mouse module was updated with data from a total of 10 references. Mouse model annotation highlights include:
- Nlgn3 Neuroligin-3-R451C mutant mice show increased microglial density in the dentate gyrus, decreased astrocyte branch length, astrocyte number of branch points, astrocyte cell radius and area in the dentate gyrus, regional changes in pre- and postsynaptic protein expression in the cortex, striatum and cerebellum including increased striatal postsynaptic density 95 (PSD-95) protein levels, and decreased cortical expression of synaptosomal-associated protein 25 (SNAP-25). There was no change reported in dentate gyrus morphology or astrocyte density (Matta, Moore, Walker, Hill-Yardin, & Crack, 2020).
- Shank3 Humanized chimeric mouse model with neural precursor cells from a Shank3 patient transplanted into the cortex shows reduction in cell soma size, decrease in axonal projections at 30 days post-transplantation andno change in dendritic spine morphology or spine density (Vitrac et al., 2020).
- Nbea Nbea heterozygous mice show increased LTP of the granule cell population spike, decreased EPSP-spike coupling, but no change in basal excitatory transmission at PP?GC synapses, synapse numbers, short-term plasticity, or network inhibition (Muellerleile et al., 2020).
- Chd8 Chd8V986* heterozygoud mutant mice show macrocephaly, reduced rearing responses, increased anxiety in the open field, increased social novelty preference, increased mortality in het mutants when the mutant parent was female, reduced transcripts in pathways associated with synaptic and neuronal projections and sodium channel activity in the cortex of embryonic but not postnatal het mutants, reduced expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) at 12 months, and increased expression of genes associated with the c-MET signaling pathway (Jimenez et al., 2020).