*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 17 new genes were added to the Human Gene module, bringing the total number to 1188. In depth annotation of 584 rare variants and 1334 common variants was also completed, and 74 new references were added. Noteworthy genes added include:
Analysis of 135 probands from a consanguineous cohort recruited for the Simons Recessive Autism Cohort (SRAC) identified six families with segregating loss-of-function variants in ACTL6B, encoding a component of the BAF complex (Wenderski et al., 2020). Bell et al. (2019) had previously reported that individuals harboring biallelic mutations in ACTL6B presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed speech, hypotonia, and autism or autistic features.
Mattioli et al. (2020) reported six individuals with frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability, motor and speech delay, autistic features, hypotonia, feeding difficulties, and spasticity or ataxic gait.
De novo missense variants in SETD1A were identified in two ASD probands (Yuen et al., 2017), while a de novo likely gene-disruptive variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). Kummeling et al. (2020) reported 15 individuals with de novo SETD1A variants presenting with a novel neurodevelopmental syndrome characterized by global developmental delay and/or intellectual disability, behavioral abnormalities, and craniofacial dysmorphisms. Of 14 individuals in this cohort, 3 presented with autistic behavior.
Gene Scoring module
For new genes, a score of S was assigned to NOVA2, RSRC1, GALNT2, FBRSL1, and SOX6. A score of 3 was assigned to SYBU, TFB2M, TBX22, IGF1, ENPP1, SYP, LAS1L, CHM, and XRCC6. A score of 3S was assigned to SETD1A, RIMS2, and POLR3A.
Copy Number Variant (CNV) module
A total of 7 newly curated references and 43 individual case records were added to the CNV module, resulting in a total of 634 curated references.
Animal Models module
The mouse module was updated with data from a total of 11 references. Mouse models derived from new risk genes include: Nr2f1, Actl6b, Sybu, and Rab39b.
Mouse model annotation highlights include:
- Nr2f1 heterozygous mice (Zhang et al., Cell Reports, 2020) show E/I imbalance of neurons in the primary somatosensory cortex, impaired social interaction, impaired social memory, repetitive self-grooming, anxiety, decreased spatial memory, but no change in motor coordination. Treatment with GinkgolideA in adult mice restored sociability, social memory, ameliorated self-grooming, improved spatial memory, and decreased anxiety, all in the short but not long term.
- Actl6b knockout mice (Wenderski et al., PNAS, 2020) show decreased survival, corpus callosum hypoplasia, thinner myelin sheaths, decreased sociability, impaired spatial memory, hyperactivity, and repetitive behaviors.
- Rab39b hemizygous mice (Zhang et al., Genes Dev, 2020) show defects in cortical neurogenesis, macrocephaly, decreased body weight, no change in anxiety, increased ambulation, decreased social memory, and decreased motor learning.