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Simons VIP: Variation in Individuals Project

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The genetics of autism is complex and involves mutations in hundreds of genes, each of which accounts for a small percentage of autism. This heterogeneity in etiology makes it challenging to perform cohort studies in autism because associations may or may not be observed depending on the sample size and composition of any one particular patient cohort.

To probe the relationship between genotype and phenotype 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 travel by individuals and families to 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 DNA extraction from blood samples. 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.

Table 1. Individuals with copy number variants (CNVs) in 16p11.2 or 1q21.1 are being studied in Phase 1 of the Simons VIP. Phase 2 includes individuals with mutations in 37 single genes.

Phase 1: Copy number variants

16p11.2 deletions

16p11.2 duplications

1q21.1 deletions

1q21.1 duplications

Phase 2: Genes associated with features of autism

ACTL6B

CHD8

KDM6B

PTEN

ADNP

CTNNB1

KDM5B

REST

ANK2

CUL3

KMT2C

SCN2A

ANKRD11

DSCAM

KMT2E

SETD5

ARID1B

DST

MBD5

SMARCC1

ASH1L

DYRK1A

MED13L

SMARCC2

ASXL3

FOXP1

PBRM1

SUV420H1

BAF190

GRIN2B

POGZ

SYNGAP1

BCL11A

KATNAL2

PTCHD1

TBR1

CHD2

Phase 2 – now underway – involves the collection of family, medical, developmental and behavioral information through online surveys and phone interviews by and with families. Phase 2 will permit expansion of the study by obviating the need for family travel and by enabling collection of longitudinal data. Importantly, this new phase will permit the rapid integration and study of new groups with recurrent genetic changes other than 16p11.2 and 1q21.1 deletions and duplications. To date, 37 single genes associated with developmental delay and features of autism have been incorporated into Phase 2 of the study (see Table 1).

Detailed medical history, phenotyping data and biospecimens for families (137 carriers of the 16p11.2 deletion and 127 carriers of the duplication; 23 carriers of the 1q21.1 deletion and 27 carriers of the duplication) are now available to researchers through SFARI Base, and new data are added quarterly. Whole-exome sequencing data are available for 507 Phase 1 participants. Structural and functional brain MRI images are available for many participants in the first phase of the study.

A paper published in Neuron further details the motivation behind the project and its design. To download "Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders," click here.

Research publications resulting from the Simons VIP can be found here.


Simons VIP data:

All Simons VIP data (including whole-exome sequencing data from 507 individuals) are available to approved researchers via SFARI Base.


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