*Notes prepared by Eric Larsen, Senanu Spring-Pearson, Marcel Estevez, Anjali Sarkar, Girish Nagendara, and Sharmila Banerjee-Basu of MindSpec, Inc., and edited by Alan Packer of SFARI.
Human Gene module
A total of 10 new genes were added to the Human Gene module, bringing the total number to 1089. In depth annotation of 436 rare variants and 10 common variants was also completed, and 73 new references were added. Noteworthy genes added include:
A de novo loss-of-function variant in BRSK2 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was found in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al. (2019) identified rare heterozygous variants in BRSK2 in nine individuals who presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities.
Read more here: BRSK2
Bell et al. (2019) reported individuals harboring biallelic mutations in ACTL6B who presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies, and minor facial dysmorphisms.
Read more here: ACTL6B
Gene Scoring module
Updated scores, and a new, simplified scoring system will be unveiled in the fall of 2019.
Copy Number Variant (CNV) module
A total of 5 newly curated references and 52 individual case records were added to the CNV module, resulting in a total of 609 curated references and 2,291 CNV loci.
Animal Models module
The mouse module was updated with data from a total of 10 references. Mouse models derived from two new genes, IQSEC1 and TRIO, and one new CNV, 3q29, were added to the database. Several high confidence genes, including SHANK3, DYRK1A, and SCN2A, have been updated with new mouse models and/or new phenotypic data. Additional models of maternal immune activation were also added.
The rat module was updated with six new models extracted from three recent publications. Additionally, an existing maternal immune activation model was updated with new information
Mouse model annotation highlights include:
C57Bl/6 mice with a CRISPR/Cas9-mediated heterozygous deletion of 20 of the 21 genes in the human 3q29 CNV introduced into a syntenic region on mouse chromosome 16 show reduced body weight, impaired social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sexual dimorphism (Rutkowski et al., Mol. Psych., 2019).
See 3q29 mouse model
Mice harboring the humanized A350V mutation in IQSEC2 show reduced surface expression of GluA2 AMPA receptors in mouse hippocampal tissue, reduced basal synaptic transmission in the hippocampus, increased locomotion, abnormal social behavior and spatial learning defects (Rogers et al., Front. Mol. Neurosci., 2019).
See IQSEC2 mouse model
Heterozygous DYRK1A mice show defective social interactions, stereotypic behaviors, epileptic activity, decreased cortical lamination, altered proportions of excitatory and inhibitory neocortical neurons and synapses, and abnormal regulation of activity of developmental genes involved in neuronal differentiation (Arranz et al., Neurobiol. Dis., 2019).
See DYRK1A mouse model