The genetics of autism is complex and involves mutations in hundreds of genes, each of which accounts for a small percentage of autism.
To probe the phenotype of genetically well-defined subtypes of autism more deeply, SFARI launched the Simons Variation in Individuals Project (Simons VIP). The project aims to identify and study large numbers of individuals sharing recurrent genetic variants known to increase the risk of developing autism spectrum and other neurodevelopmental disorders. Longer-term goals are to use these data to develop targeted interventions and focused clinical care.
The Simons VIP first studied individuals with a deletion or duplication of chromosomal segment 16p11.2, the study’s immediate goal being to identify medical, cognitive, neural and behavioral profiles shared by those in this group.
Phase 1 of this project, which ended in early 2014, involved in-person evaluations at clinical study sites. There, participants underwent extensive psychological and neurological testing, along with neuroimaging — including magnetic resonance imaging (MRI), functional MRI, and magnetoencephalography (MEG) — with a uniform protocol and collection of biospecimens. DNA was extracted from whole-blood for genetic experiments. Fibroblasts were cultured and cryopreserved for distribution to researchers interested in making induced pluripotent stem cells (iPSCs) or for other experiments. As a pilot project, Phase 1 also included testing a small number of 1q21.1 deletion and duplication carriers using the identical protocol (see Table 1).
Phase 2 – currently recruiting – involves the collection of family, medical, developmental and behavioral information through online surveys and phone interviews with families. Phase 2 permits expansion of the study by obviating the need for family travel and by enabling collection of longitudinal data. Importantly, this new phase permits the rapid integration and study of new groups with recurrent genetic changes other than 16p11.2 and 1q21.1 deletions and duplications. To date, 53 single genes associated with neurodevelopmental differences and features of autism have been incorporated into Phase 2 of the study (see Table 1).
Table 1. Individuals with copy number variants (CNVs) in 16p11.2 or 1q21.1 are being studied in Phases 1 and 2 of the Simons VIP. Phase 2 also includes individuals with mutations in 53 single genes.
|Phases 1 and 2: Copy number variants|
|16p11.2 deletions||16p11.2 duplications|
|1q21.1 deletions||1q21.1 duplications|
|Phase 2: Genes associated with features of autism and developmental delay|
Data from the following individuals are currently available to approved researchers via SFARI Base.
Copy number variants (individuals enrolled in Phase 1 and/or Phase 2):
- 253 carriers of the 16p11.2 deletion
- 172 carriers of the 16p11.2 duplication
- 62 carriers of the 1q21.1 deletion
- 51 carriers of the 1q21.1 duplication
Single genes (all individuals enrolled in Phase 2):
- 15 individuals with ADNP mutations
- 26 individuals with ASXL3 mutations
- 7 individuals with CHAMP1 mutations
- 5 individuals with CHD8 mutations
- 10 individuals with CSNK2A1 mutations
- 12 individuals with DYRK1A mutations
- 30 individuals with GRIN2B mutations
- 10 individuals with HIVEP2 mutations
- 11 individuals with HNRNPH2 mutations
- 14 individuals with MED13L mutations
- 20 individuals with PACS1 mutations
- 28 individuals with PPP2R5D mutations
- 83 individuals with SCN2A mutations
- 8 individuals with SETBP1 mutations
- 32 individuals with STXBP1 mutations
- 23 individuals with SYNGAP1 mutations
Genetic data are available for a subset of individuals and their families enrolled in Phase 1. More information is available in SFARI Base and in the publications listed below:
Single nucleotide polymorphism (SNP) genotype data
- Duyzend M.H. et al. Am. J. Hum. Genet. 98, 45-57 (2016) PubMed, Data available through SFARI Base and NDAR
Targeted sequencing data
- Nuttle X. et al. Nature 536, 205-209 (2016) PubMed, Data available through SFARI Base (targeted sequencing around the 16p11.2 rearrangement breakpoints; please reference accession SFARI_SVIP_MIPS_1)
- Fiddes I.T. et al. Cell 173, 1356-1369 (2018) PubMed (targeted sequencing around the 1q21.1 rearrangement breakpoints; please reference accession SFARI_SVIP_VSV_1)
Whole-exome sequencing data
- Daly M.J. et al. (in preparation) Data available through SFARI Base
Whole-genome sequencing data
- A paper published in Neuron further details the motivation behind the project and its design; click here to download the article
- Read more about the Simons VIP in the Simons Foundation 2016 Annual Report
- Publications resulting from Simons VIP data are available here (select the filter “Uses Resources From: Simons VIP”)
- Families interested in participating in the Phase 2 study can register online at Simons VIP Connect (or call 855-329-5638 for more information)
- Simons VIP Investigators
- Researcher welcome packet (PDF)
- How to access SFARI Base and request SFARI resources
- Biospecimen prices
- List of neuropsychological tests and other phenotypic instruments used in the Phase 1 study (PDF)
- Definition of phenotypic data points for Simons VIP (xls)
- Simons VIP Institutional Review Protocol (PDF)
- Simons VIP (Phase 1) consent form (PDF)
- Simons VIP (Phase 2) consent form (PDF)
- Induced pluripotent stem cell lines from Simons VIP participants