The genetics behind autism have long been a challenge to untangle. When Simons Searchlight began 15 years ago, it aimed to establish resources for scientists to study the impact of genes linked to autism and neurodevelopmental disorders. Today, it has grown into a large bank of resources including genetic, phenotypic and clinical data, along with biospecimens and research support tools to recruit and study individuals with genetic variants in more than 180 autism-related genes.

“What’s unique about Simons Searchlight is that instead of focusing on just one gene, it includes many different genes,” says Kelsey Martin, executive vice president of autism and neuroscience at the Simons Foundation. “That breadth gives us the ability to look across many individuals with different genetic variations to understand where there are commonalities and where they diverge.”

Researchers can access Simons Searchlight data and other resources for their studies through SFARI Base. For those needing participants, Research Match offers a streamlined way to recontact families, reducing recruitment barriers and enabling studies that would otherwise be difficult in rare genetic conditions. Together, these platforms empower researchers to move quickly from idea to implementation, leveraging a global community of participants and one of the most comprehensive autism genetics resources available.

Starting with Simons VIP

In its early years, Simons Searchlight, then called the Simons Variation in Individuals Project (Simons VIP), focused on the most recurrent genetic contributor to autism known at the time: 16p11.2 duplication or deletion.

“Some of the early, large studies looking for genetic causes for autism and neurodevelopmental disorder risks identified a region on chromosome 16 containing a couple dozen genes that can either be duplicated or deleted in different individuals,” says Simons Searchlight Principal Investigator Wendy Chung of Boston Children’s Hospital. “Remarkably, even after extensive studies examining many other genes involved in autism, this region still accounts for about one percent of individuals with autism. While one percent might sound small, it’s actually quite significant for a single genetic factor, especially considering that there are likely over 500 genes and copy number variants associated with autism.”

Diving deep into 16p11.2 gave scientists an opportunity to better understand what is otherwise a highly heterogeneous condition by studying it in association with a single genetic factor.

This phase of Simons Searchlight led to significant advancements, including the discovery that even among individuals with the same genetic diagnosis, there is significant phenotypic variability, including behavioral differences and physiological variability observed in MRI and EEG studies.

This variability, along with the ability to use results of whole exome sequencing in large cohorts and the increasing identification of single gene contributors to autism, prompted Simons Searchlight to pivot its focus. In Phase 2, the program began surveying across many genes, aiming to better understand where there might be similarities and differences in phenotypes and biological mechanisms across distinct genetic disorders associated with autism.

The study’s subsequent phase, now known as Simons Searchlight (or Phase 2), involves more than 9,000 participants from 94 different countries, with genetic variants in more than 185 genes. While the original Simons VIP conducted in-person assessments at three clinical sites, Phase 2 shifted to use online measures and sample collection at a lab near home or family and research conferences.

Genetic and Phenotypic Data

For a subset of participants with 16p11.2 duplication or deletion, Simons Searchlight offers single-nucleotide polymorphism (SNP) genotype data, targeted sequencing data, whole-exome sequencing data and whole-genome sequencing data. Currently, Phase 2 offers clinical genetic reports verifying participants carry a genetic variation in one of Searchlight’s eligible genes.

Martin emphasizes that this genetic data is important because while people may be grouped under one gene, there are many genetic variants within that gene that could be useful to study.

“When a given gene is associated with autism, there can be many different variants within the gene. All of these variants are grouped together under that gene, but within the group, there’s a wide range of different types of variants that may have different effects on the protein function,” says Martin.

And while Simons Searchlight studies many rare conditions, the exact same variants can occur in many people, thereby providing a unique insight into often understudied conditions.

Both Simons VIP and Phase 2 provide phenotyping data, including family medical, developmental and behavioral information. Some participants have completed repeated longitudinal measures semiannually (prior to 2016 for children under age 7) or annually (for child carriers over age 7), including medical history, Vineland Adaptive Behavior Scale, diagnostic updates and more. This longitudinal data collection is essential, as it allows researchers to track changes over time, identify developmental patterns and better understand how these genetic conditions evolve.

“I think the potential scale of Simons Searchlight is also really exciting, because it may allow us to power genotype–phenotype analyses in a way that truly reveals meaningful correlations,” says Julia Sommer, SFARI senior scientific officer.

Martin also hopes that researchers studying these genes in animal models will take advantage of Simons Searchlight’s data in humans to dive deeper and gain new insights. “Whether it’s in mice, rats or zebrafish, Simons Searchlight offers an incredible opportunity for researchers to bridge experimental model systems with what’s happening in human beings.”

Biospecimens

Simons Searchlight’s biorepository is a vital resource for researchers, offering high-quality samples to drive new discoveries. For a subset of Simons VIP participants, this includes fibroblasts, induced pluripotent stem cells (iPSCs) and DNA. For a subset of Phase 2 participants, this includes DNA, peripheral mononuclear blood cells (PBMCs), lymphoblastoid cell lines (LCLs) and iPSCs.

“I think having these biospecimens, especially iPSCs, available to researchers is incredibly valuable, because you can use them to generate many cell types, and we could hopefully one day use them to enable studies of interactions between the dominant mutation, or what we think is the causative mutation, and other genes in an individual’s background,” says Sommer.

“iPSCs also enable research where we can connect biochemical and cellular biological processes to data we have from participants in the Simons Searchlight data repository,” adds Martin. “I think that combination is unique.”

One example of a study made possible with Simons Searchlight iPSCs comes from The Broad Institute’s Samouil Farhi and Ralda Nehme, who are leveraging the resource to link autism risk genes to their effects on human neurons using scalable “fingerprinting” assays and optical assays to detect changes in cellular morphology and physiology. The team is comparing profiles across many autism-associated genes studied in Simons Searchlight, hoping to reveal shared biological pathways and mechanisms.

“A particularly important aspect of the project is confirming that knockout phenotypes generated by CRISPR match the phenotypes observed in loss of function genetic backgrounds of real individuals with autism, made possible by the Simons Searchlight collection’s large representation of autism risk alleles,” says Farhi.

“I think that’s a project that exemplifies how scientists can leverage the scale of this resource to look at multiple genes rather than just one,” says Sommer.

Research Match

Research Match is a service that allows researchers to recontact participants in SFARI cohorts, including Simons Searchlight, for new studies. To date, more than 1,700 Simons Searchlight families have joined studies through Research Match.

One example of a study made possible by Research Match comes from Thomas Frazier of John Carroll University, who recontacted Simons Searchlight participants to conduct a study using webcams and artificial intelligence techniques to explore how individuals with rare genetic conditions display receptive language, sustained attention, social attention, joint attention, processing speed, and single-word reading, finding impairments in many of these measures.

“Research Match has been a huge benefit for our research because it facilitates participant recruitment and decreases the amount of information that needs to be collected,” says Frazier. “This makes the research process so much more efficient and leads to well-powered research with detailed information collected from participants.”

“[Research Match] is a really valuable opportunity, especially because people with rare diseases are, by definition, rare and geographically dispersed,” says Jennifer Foss-Feig, SFARI vice president and senior scientific officer. “So, for a researcher working locally, running a study could be very challenging. Research Match provides a platform to connect with potential study participants from across the U.S. and globally, whether in English or one of six other languages. This makes it possible to build a meaningful sample size that would be difficult to achieve otherwise.”

Engaging with Patient Advocacy Groups

One of Simons Searchlight’s most powerful resources are through its partnerships with patient advocacy groups (PAGs). Simons Searchlight and SFARI help connect scientists studying autism or related neurodevelopmental disorders with those directly affected by them, which can open new avenues for research.

“Scientists who normally work with rats and mice suddenly find themselves attending a family meeting and actually interacting with those affected by what they study, which they often find incredibly moving and inspirational,” says Martin. “This experience can provide insights into where there are gaps in research by highlighting the issues that matter most to those affected.”

“This was a great experience,” says Dan Feldman, a professor at the University of California, Berkeley who studies disorders related to SCN2A and attended a FamilieSCN2A meeting last year. “I learned a lot about the children’s life experiences and medical challenges, and also about the families’ priorities and what they hope to gain from research.”

The meetings also serve as an opportunity for Simons Searchlight to recruit participants, without whom Simons Searchlight’s research would not be possible.

“Advancing the science depends on our participants, who have been so generous with their insights, their samples, and their time,” says Martin. “We are grateful to have them as partners in this shared goal of advancing research.”

For more information, visit Simons Searchlight or email the SFARI Data and Biospecimen Repository (SDBR) team at [email protected]. Data and biospecimens are requested through SFARI Base.