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Publications

Date Revised: July 2025

Thank you to all the families for participating in Simons Searchlight. Through your involvement, we aim to assist researchers and geneticists worldwide in understanding genetic disorders affecting you or your family.

The research conducted using Simons Searchlight data has resulted in numerous published papers. These papers undergo a peer-review process, where other scientists assess and validate the research before publication in scientific journals. Additionally, some findings are shared via preprints, allowing rapid dissemination of information to the scientific community.

Many of the publications feature the name “Simons Variation in Individuals Project” (SimonsVIP), which was the original name of our research program, now known as Simons Searchlight.

The listed articles are organized from newest to oldest. You can explore publications by specific genetic conditions using the categories below.

As of June 2025, Simons Searchlight has contributed to 121 publications and preprints, and we will continue to summarize new publications.

For accessibility, the Simons Foundation encourages researchers to make their publications open access. If you cannot access a journal article, we recommend reaching out to the last author listed on the paper to request a copy.

Understanding Publication Reference Titles:

-The article title is followed by publication details, including where and when it was published.
– If there are more than three authors, we use “et al.” to represent additional contributors.
– Journals are referenced using shorthand names.

Disclaimer: Please be aware that papers posted on medRxiv (pronounced med-archive) or bioRxiv (pronounced bio-archive) are not peer-reviewed or edited before online publication. In contrast, all other articles listed here have undergone review by fellow researchers to ensure quality and accuracy. While posting on medRxiv or bioRxiv allows researchers to share findings quickly, the final published results may differ after undergoing formal peer review for journal publication.

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Genetic Condition
Year of Publication
121 Publications
Cell-type specific global reprogramming of the transcriptome and epigenome in induced neurons with the 16p11.2 neuropsychiatric CNVs
  • Mental health conditions, such as schizophrenia or anxiety, can be inherited, and researchers have been working to understand what factors may be inherited from family members.Show More
  • Since 16p11.2 deletions and 16p11.2 duplications have been linked to mental health conditions, the researchers used nine 16p11.2 deletion and five 16p11.2 duplication induced pluripotent stem cells (iPSCs) derived from Simons Searchlight participants. iPSCs are a special type of cells that can be turned into other body cells, making it easier to study parts of the body that are difficult to get samples of, such as brain cells.
  • These iPSCs were turned into different brain cells to learn which genes were turned on or off (also known as gene expression) that might lead to mental health conditions. The researchers also studied the presence of DNA methylation, a process where chemical tags are added to DNA to “silence” or turn off a genetic region.
  • Brain cells and neurons with a 16p11.2 deletion had genes within the 16p11.2 region that were less active. Whereas, brain cells and neurons with a 16p11.2 duplication had genes within the 16p11.2 region that were more active.
  • Importantly, genes outside the 16p11.2 region were also affected by changes in gene expression and DNA methylation, usually in the same direction (levels either went up in both deletions or duplications, or went down).
  • The PCSK9 gene did not follow this pattern. Gene expression in iPSCs was higher in 16p11.2 deletions and lower in 16p11.2 duplications. But, in neurons, gene expression was higher in both 16p11.2 deletions and 16p11.2 duplications. The researchers suggested that the PCSK9 gene could affect head size, brain development, and body size in people with a 16p11.2 variant.
  • To study this, the researchers used a fish model to study the PCSK9 gene, and they found that turning off the PCSK9 gene resulted in changes in embryonic and early brain development.
  • The researchers also found that in iPSCs and neurons, in both 16p11.2 deletions and 16p11.2 duplications, there was often more DNA methylation compared with cells without these variants, across many locations of DNA.
  • This work used advanced iPSC technology to help us better understand the bigger picture of what DNA in brain cells looks like in people with 16p11.2 deletions and 16p11.2 duplications.Show Less
Eur J Hum Genet Epub ahead of print, (2025)
Ward et al.
Full Article

16p11.2 deletion
16p11.2 duplication
2025

Comparison of autism domains across thirty rare variant genotypes
  • The researchers investigated how likely it is to develop autism across individuals with: idiopathic autism (autism with no known genetic cause), monogenic conditions (a genetic variant affecting only one neurodevelopmental gene), copy number variant conditions (larger deletions or duplications that include several genes, also called CNV), and control participants (people with no developmental or genetic diagnosis). Show More
  • The researchers collected Social Communication Questionnaire (SCQ) data from multiple cohort studies to examine the differences and similarities across groups. The SCQ is used as a tool to assess autism features in large research cohorts. A score of 22 or higher identifies that a person should have a clinical evaluation of autism, meaning that the survey is not able to provide someone with an autism diagnosis.
  • Lifetime SCQ data from 364 participants in Simons Searchlight, 309 people across 15 monogenic conditions, and 55 people across 5 CNV conditions were combined with SCQ data from other research studies.
  • The likelihood of autism was higher across monogenic conditions, with people having greater impairment than those with CNV conditions. ADNP and DYRK1A with the highest prevalence of autism.
  • Subdomains of the survey, which included communication, social, and repetitive behaviors were evaluated to see if there were differences within the various genetic conditions. This review found that there were relative strengths for certain genetic communities, such as 1q21 duplication carriers and communication, 16p11.2 deletion carriers and social domains, and HNRNPH2-related syndrome carriers and repetitive behaviors. There were also relative challenges for certain communities, such as communication for people with STXBP1-related syndrome, social behaviors for people with SCN2A-related syndrome, and repetitive behaviors for people with ASXL3-related syndrome and 15q11.2 deletion carriers.
  • The researchers noted that in general, the variability of the SCQ subdomain scores were greater within the results of people with a particular genetic condition, as compared with across genetic conditions. This suggests that a rare neurodevelopmental genetic variant on its own cannot predict if someone is going to have autism, and other genetic or environmental factors likely play a role.
  • This work was supported in part by a SFARI grant.Show Less
EBioMedicine 112, 105521 (2025)
Ali et al.
Full Article

15q11.2 deletion
16p11.2 deletion
16p11.2 duplication
1q21.1 deletion
1q21.1 duplication
ADNP
ASXL3
CTNNB1
DYRK1A
GRIN2B
HIVEP2
HNRNPH2
MED13L
PACS1
PPP2R5D
SCN2A
SETBP1
SLC6A1
STXBP1
SYNGAP1
2025

Clinical characteristics, longitudinal adaptive functioning, and association with electroencephalogram activity in PPP2R5D-related neurodevelopmental disorder
  • The researchers used Simons Searchlight data in combination with data collected at clinics. This included data from 42 people with pathogenic/likely pathogenic PPP2R5D variants.Show More
  • Six Simons Searchlight surveys were included: Annual Medical History Survey, Vineland-3, Child Behavior Checklist, Social Responsiveness Scale Second Edition, Children’s Sleep Habits Questionnaire, and Quality of Life Inventory - Disability.
  • The data from Simons Searchlight showed that people with PPP2R5D-related syndrome had low adaptive functioning (with gains in functioning over time), behavioral challenges, high rate autism, and sleep issues. Caregivers often reported macrocephaly, hypotonia, developmental delay, global developmental delay, or intellectual disability. About half of people had seizures and reported clinical EEG findings.
  • Clinic evaluations confirmed macrocephaly and hypotonia, low cognitive levels, and motor difficulties.
  • Caregiver burden was measured through a survey and the researchers found that 80 percent (20 out of 25 caregivers) were at risk of burnout.
  • EEGs were conducted by the researchers and the results were compared with a survey called the Vineland-3. EEGs give a readout of brain activity through a set of different waves. These waves look different if a person is awake or asleep because the brain function is different during those times. Two waves that are important for being awake and alert are called the beta and gamma waves.
  • The researchers found that people with PPP2R5D-related syndrome who had more EEG beta waves had lower adaptive behavior scores on the Vineland-3 survey, more behavior challenges, and sleep difficulties. People with PPP2R5D-related syndrome who had more EEG gamma waves had lower Vineland-3 communication scores.
  • This research, along with some other research on EEGs, supports the use of EEG signatures as potential biomarkers for other medical features outside of seizure activity.
  • The researchers suggested that people with the p.Glu200Lys variant had milder medical features compared with people with other PPP2R5D variants.Show Less
Clin Genet 107, 34-43 (2025)
Sudnawa et al.
Full Article

PPP2R5D
2025

Copy number variants and the tangential expansion of the cerebral cortex
  • This study used brain imaging from several different genetic cohort studies to see if there was a relationship between cortical surface area and copy number variant genetic variation. The researchers also wanted to see if region-specific, cell-specific, and time-specific gene expression played roles in shaping the development of cortical surface area.Show More
  • Cortical surface area refers to the outer area of the brain region, which is called the cortex (also known as the cerebral cortex). This is the outermost layer of the left and right sides of the brain. During the process of brain development starting in utero, the brain develops folds and this results in more surface area of the brain structure. Abnormal development of the cortical surface area is linked to neurodevelopmental conditions.
  • The cortical surface area is part of the brain that is important for thinking, voluntary movements, language, reasoning, and perception.
  • The researchers used Simons VIP (Simons Searchlight from 2010-2014) MRI brain imaging data from people with 16p11.2 deletions and duplications, people with 1q21.1 deletions and duplications, and family members without deletions or duplications. The study also included MRI brain imaging data from other research groups.
  • The researchers found that people with 16p11.2 or 1q21.1 deletions or duplications had a smaller cortical surface area compared with people without these copy number variants. People with 16p11.2 or 1q21.1 deletions had a smaller cortical surface area compared with people with these duplications.Show Less
Nat Commun 16, 1697 (2025)
Liao et al.
Full Article

16p11.2 deletion
16p11.2 duplication
1q21.1 deletion
1q21.1 duplication
2025

Differential links in 16p11.2 deletion carriers reveal aberrant connections between large-scale networks
  • The researchers used imaging and survey data from 26 Simons Searchlight participants with a 16p11.2 deletion and 41 age-matched people without a genetic diagnosis to investigate the brain connectivity differences in each group.Show More
  • The researchers studied the different brain patterns that light up on the MRI, which is called functional connectivity.
  • People with a 16p11.2 deletion had different functional connectivity of the brain than people with no genetic diagnosis. One hot spot of activity in people with a 16p11.2 deletion was linked to the region of the brain needed for processing speech sounds, which is similar to findings in other research studies.
  • The researchers also found other patterns, such as the way the brain lights up differently for people with lower communication and social adaptive behaviors.Show Less
Cereb Cortex 35, bhae474 (2025)
Qureshi et al.
Full Article

16p11.2 deletion
2025

Direct pathway bias and altered striatal neurogenesis in human iPSC models of 16p11.2 CNVs: Evidence from single-cell and functional analyses
  • The researchers investigated how a specific brain pathway called a striatal circuit is changed in people with a 16p11.2 deletion or duplication. A striatal circuit controls motor movement and is influenced by thoughts, emotions, and personal motivations.Show More
  • The researchers used 3 16p11.2 deletion and 3 16p11.2 duplication induced pluripotent stem cells (iPSCs) from Simons Searchlight participants. The researchers turned the iPSCs into striatal brain cells in the lab.
  • The researchers found that striatal 16p11.2 deletion cells divided more often and took longer to divide than cells with no genetic condition, and that striatal 16p11.2 duplication cells divided less often and faster than cells with no genetic condition. The researchers suggested that these reciprocal features of the cells are consistent with what has been reported in humans with deletion carriers having a larger than average head size and duplication carriers having a smaller than average head size.
  • Even though the cells behaved differently when growing and dividing, the researchers found that these copy number variant striatal cells favored one subtype in both deletion and duplication carriers. This could explain why having a deletion or duplication can be linked to similar neurodevelopmental conditions, such as autism, intellectual disability, and ADHD.Show Less
bioRxiv Preprint, (2025)
Fjodorova et al.
Full Article

16p11.2 deletion
16p11.2 duplication
2025

Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility
  • Many people with neurodevelopmental conditions experience gastrointestinal (GI) issues, such as constipation and diarrhea.Show More
  • The researchers in this study used a combination of Simons Searchlight genetic and clinical data, human tissue samples, and a frog model to study how genetic variants associated with autism affect the GI system.
  • The researchers looked at the percent of people who had GI symptoms and one of the following conditions: SYNGAP1, CHD8, ADNP, SCN2A, FOXP1, CHD2, GRIN2B, ARID1B, SLC6A1, DYRK1A, STXBP1, MED13L, CTNNB1, ANKRD11, CSNK2A1, and PACS1. GI issues were reported for all of these conditions, and the average frequency of GI issues was about 52 percent.
  • The genetic conditions and GI issues identified were similar to those identified using Citizen Health medical record data for the 5 genes with available Citizen data: SYNGAP1, CHD8, SCN2A, CHD2, and DYRK1A. Within these 5 genetic conditions, gut dysmotility, and specifically constipation, were the most common GI issues. GI motility is controlled by neurons in the GI tract (known as the enteric nervous system). The researchers think that genetic variants in these genes might affect the development or function of the enteric nervous system.
  • The researchers then used frog models for SYNGAP1, CHD8, SCN2A, CHD2, and DYRK1A. Genetic variants in these genes affected the early development of the enteric nervous system. This suggests that even though these genes work in different cellular pathways, they can affect this early developmental process.
  • Finally, the researchers found that a depletion of DYRK1A resulted in gut dysmotility. The researchers treated the frogs with drugs that affect serotonin. Serotonin is a chemical that works as a signal between brain cells. It also controls the enteric nervous system and gut motility. The researchers were able to return gut motility to normal in the frog model.
  • This research furthers our understanding of the link between GI symptoms and autism-associated genes.Show Less
Nat Commun 16, 2238 (2025)
McCluskey et al.
Full Article

ADNP
ANKRD11
ARID1B
CHD2
CHD8
CSNK2A1
CTNNB1
DYRK1A
FOXP1
GRIN2B
MED13L
PACS1
SCN2A
SLC6A1
STXBP1
SYNGAP1
2025