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Publications

Date Revised: August 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 August 2025, Simons Searchlight has contributed to 125 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Please be aware that papers posted on medRxiv (pronounced med-archive) or bioRxiv (pronounced bio-archive) are not peer-reviewed or edited before online publication.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
125 Publications
Clinical and neuropsychological phenotyping of individuals with somatic variants in neurodevelopmental disorders
  • The researchers studied Simons Searchlight participants who were mosaic for neurodevelopmental genetic variants.Show More
  • Being mosaic for a genetic variant means that a person has some cells with the genetic variant and other cells that do not have the genetic variant. People who are mosaic for a genetic variant have a genetic change that happened after conception, but usually during the earlier stages of pregnancy. These changes happen spontaneously and are not a result of something that happened or was taken during pregnancy.
  • For people who are mosaic for a genetic variant, the number of cells with the genetic variant is different in different parts of the body. For example, when doing genetic testing on a person's blood sample, the amount of cells with the genetic variant might be different than if using another tissue type for genetic testing.
  • The researchers use the term ‘somatic’ to indicate someone who is mosaic for a neurodevelopmental gene, and ‘germline’ to indicate someone who is born with only the genetic variant detected.
  • 15 people with pathogenic or likely pathogenic mosaic variants across 10 genetic disorders were identified in Simons Searchlight. The genes affected were CHD8, HIVEP2, SCN2A, STXBP1, SYNGAP1, CTNNB1, IRF2BPL, NEXMIF, PPP2R1A, and distal 16p11.2 deletion. Eight people had detailed clinical information available.
  • People who were mosaic for pathogenic or likely pathogenic variants showed a spectrum of medical conditions and traits. All people had diagnoses of developmental delay and/or language delay, about one-half had hypotonia and/or autism diagnoses, and smaller subsets of people had diagnoses of epilepsy, cortical visual impairment (CVI), large head size (macrocephaly), and small head size (microcephaly).
  • People who were mosaic for pathogenic or likely pathogenic variants showed a range of adaptive functioning, social and communication skills, social and related behaviors, and emotional and behavioral symptoms.
  • The researchers did a comparison of medical features between people who were mosaic and those with germline variants (people with cells that had only the genetic variant). The results suggested that people who are mosaic for a neurodevelopmental genetic variant had either similar or less severe clinical features than those with germline variants in the same gene.Show Less
Neurol Genet 11, e200254 (2025)
Mo and Walsh
Full Article

16p11.2 distal deletion
CHD8
CTNNB1
HIVEP2
IRF2BPL
NEXMIF
PPP2R1A
SCN2A
STXBP1
SYNGAP1
2025

Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown
  • The researchers used induced pluripotent stem cells (iPSCs) derived from Simons Searchlight participants with PPP2R5D variants to understand how these variants affect neuronal development and to test a potential new treatment approach. 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.Show More
  • The researchers studied iPSCs from people with p.Glu198Lys and p.Glu420Lys variants because they suspected that people with these variants have a more severe neurodevelopmental condition than people with other PPP2R5D variants. The researchers were interested in how cells with these variants compared with a cell line with a complete deletion of the PPP2R5D gene.
  • Brain iPSCs with the p.Glu198Lys and p.Glu420Lys PPP2R5D variants grew more than iPSCs without the variants. Brain cells and neurons made from iPSCs with the variants showed increased growth of connections than brain cells and neurons made from iPSCs without the variants.
  • These variants altered genetic pathways that are involved in brain cell growth, function, and processes needed for cells to connect to each other.
  • These results were not found in the cells that had the PPP2R5D gene deletion. This suggests that the genetic condition associated with PPP2R5D-related syndrome is a result of altered function of the PPP2R5D protein, not a loss of the PPP2R5D protein.
  • Antisense oligonucleotides (ASOs) can be used to target specific pieces of RNA that make proteins. The researchers made ASOs to target only the RNA with the problematic p.Glu198Lys variant. They studied how much RNA was produced (also known as gene expression) from the targeted variant before and after ASO treatment.
  • They found that ASO treatment for p.Glu198Lys reversed the brain cell overgrowth.
  • This research provides a better understanding of the molecular and cellular effects of PPP2R5D variants, as well as insight into potential therapies.Show Less
HGG Adv 6, 100450 (2025)
Young et al.
Full Article

PPP2R5D
2025

Accessibility and utilization of genetic laboratory reports: A comprehensive analysis of factors impacting access and use across borders
  • In this Master’s thesis, the author used data from a survey created by Kaitlyn Singer, research project manager for Simons Searchlight, that was conducted between April 2022 and January 2023. Singer developed a 15-question survey designed to assess participants’ level of knowledge about their genetic condition, care received from different providers, resources received, and laboratory testing.Show More
  • The survey was sent by email blast to Simons Searchlight participants, and a total of 622 surveys were completed.
  • The author found that genetic-result disclosure appointments taking 30 minutes or less with a genetics provider correlated with a higher frequency of participants leaving with their questions unanswered. Appointment times between 30 minutes and 1 hour resulted in a higher level of appointment satisfaction.
  • Genetic result disclosures from a geneticist or genetic counselor resulted in higher levels of satisfaction. In addition, participants who received their results from a genetic counselor were more likely to report that their questions had been answered during the appointment. In contrast, those who received results from a neurologist or primary care provider were more likely to report that their questions had not been answered.
  • While most people did report receiving their genetic testing report at the time of results disclosure, about 20 percent did not receive a report at the time of disclosure.
  • Some of the data from international participants (outside the U.S.), suggested that receiving a result from a geneticist was associated with a higher proportion of participants reporting that their questions were not answered, with no differences identified between receiving a result from a genetic counselor, neurologist, or “Other” provider.
  • This research suggests that shorter appointment times with less specialized professionals might lead to more unresolved questions from families.Show Less
University of Pittsburgh ProQuest Dissertations & Theses, 31995165 (2025)
Lopez-Jimenez
Full Article

All Genes
2025

Seizures and functional deficits across Mendelian disorders of epigenetic machinery: Differential effects as a function of epigenetic modifications
  • The researchers studied neurodevelopmental conditions in Simons Searchlight that are known as Mendelian disorders of epigenetic machinery, also called chromatinopathies.Show More
  • Chromatin consists of DNA, RNA, and proteins that are arranged to help the DNA fit inside of cells. Different classes of proteins perform tasks on the chromatin to help modify access to the DNA. “Writer” proteins write or add chemical tags to the chromatin to turn a gene on or off. “Writer/reader” proteins (WRs) can write tags, but they also read the tags on the chromatin to carry out the instructions. “Chromatin remodeler/reader” proteins (CRRs) change the structure of chromatin and then read the tags to know what changes to make.
  • The goal of this study was to look at the behavior, development, and medical and diagnostic history in people with genetic variants in genes that code for and affect the function of chromatin writers, WRs, and CRRs.
  • The researchers analyzed online survey data from 71 Simons Searchlight participants with a genetically confirmed pathogenic or likely-pathogenic variant: 15 people with a writer genetic variant (includes variants in KMT5B, SETD5), 22 people with a writer/reader variant (includes variants in DNMT3A, EHMT1, KMT2A, KMT2C, KMT2E), and 34 people with a remodeler/reader variant (includes variants in ATRX, CHD2, CHD8, SMARCA4).
  • The researchers collected the following data: Simons Searchlight medical history, seizure history, previous diagnosis, medication history, and the online parent/caregiver Vineland Adaptive Behavior Scales (Vineland-3) form to evaluate adaptive functioning and development.
  • The researchers showed that adaptive functioning across most adaptive behavior skills was lowest in people with a CRR variant and highest in people with a writer variant. People with a WR variant typically scored in between those with a writer or CRR variant. People with a WR variant had significantly greater scores than those with a CRR variant, specifically in community daily living skills and play/leisure skills.
  • The researchers did not find any significant differences among the groups in diagnosis of most developmental diagnoses, history of seizures, or seizures in sleep.
  • More participants with a CRR variant reported having minimally verbal status, using rescue medication for seizures, and/or needing emergency intervention for seizures, compared with those with a writer or WR variant.
  • These results show that variants that affect chromatin remodeling are associated with more severe functional deficits across adaptive functioning domains, and that despite similar risk of seizures and other diagnoses, people with chromatin remodeling disorders have more severe seizure-related outcomes that require more intensive care.Show Less
Arch Clin Neuropsychol Epub ahead of print, (2025)
Ng
Full Article

ATRX
CHD2
CHD8
DNMT3A
EHMT1
KMT2A
KMT2C
KMT2E
KMT5B
SETD5
SMARCA4
2025

Motor impairment in children with 16p11.2-deletion and -duplication syndromes
  • The researchers analyzed Simons VIP (Simons Searchlight from 2010-2014) in-clinic assessments and caregiver-reported information to study motor function in people with 16p11.2 deletions and duplications.Show More
  • This study included data from 339 people: 121 people with a 16p11.2 deletion, 66 people with a 16p11.2 duplication, 91 people who were non-carrier siblings, and 61 unrelated people without a copy number variant (CNV).
  • The researchers analyzed doctor-administered assessments of motor skills and the ability to control and coordinate movements, including fine and gross motor skills.
  • Across all study participants, having a clinical autism spectrum disorder diagnosis, a higher severity score on the Autism Diagnostic Observation Schedule survey, and/or a clinical developmental coordination disorder diagnosis was associated with worse performance on motor assessments.
  • Across almost all motor performance assessments, people with a 16p11.2 copy number variant (CNV) had poorer motor function compared with people without a 16p11.2 CNV.
  • In most cases, there was no observed difference in motor performance between people with a 16p11.2 deletion and people with a 16p11.2 duplication. Two exceptions were that people who were deletion carriers (1) had worse motor performance on the assessment of manual dexterity, aiming and catching, and balance, and (2) had slightly higher rates of developmental coordination disorder compared with people who were duplication carriers.
  • Sex and age did not have any significant effect on motor performance and did not impact the effect of having a 16p11.2 CNV on motor performance.
  • The researchers used a nonverbal intelligence quotient (IQ) to account for any language-related difficulties. IQ was a large predictor of motor performance, but when controlling for this, 16p11.2 CNV carrier status still explained most of the motor performance effects.
  • These results taken together reveal that autism in general, and specific genetic conditions associated with autism such as 16p11.2 deletions and 16p11.2 duplications, are associated with motor impairments.Show Less
J Autism Dev Disord Epub ahead of print, (2025)
Soliman et al.
Full Article

16p11.2 deletion
16p11.2 duplication
2025

OCNDS core features are conserved across variants, with loop-region mutations driving greater symptom burden
  • The researchers examined whether the location of a genetic variant within a gene is linked to specific disease features. Show More
  • This study included 48 Simons Searchlight participants with a pathogenic or likely pathogenic missense CSNK2A1 variant.
  • The CSNK2A1 gene makes the protein casein kinase 2 alpha subunit 1 (CK2α). This protein is a subunit of the protein complex called casein kinase 2 (CK2). CK2 is a large protein complex formed by smaller proteins – two CK2α proteins and two CSNK2B (CK2β) proteins. Damaging genetic variants in the CSNK2A1 gene result in Okur-Chung neurodevelopmental syndrome (OCNDS).
  • The most commonly reported participant symptoms were speech/language disorder/delay; non-seizure neurological disorders, such as diminished muscle tone; sleep disorders; and gastrointestinal issues. Developmental patterns (based on Vineland-3 scores) were also universally delayed.
  • Most participants (83 percent) had serious sleep disturbances that qualify as a pediatric sleep disorder. Caregivers reported sleep disruption as one of the three most problematic symptoms.
  • To examine associations between a genetic variant and clinical outcomes, the researchers categorized the variants into one of 10 known protein domain segments. Currently, two subsegments of the CK2α protein have no known CSNK2A1 missense variants. The activation segment (region 175-200 of CK2α) had the highest number of participants in what is called the p + 1 loop, which includes the most common recurring variant, p.Lys198Arg. The second largest group was the Glycine (Gly)-rich binding loop, region 45-53 of CK2α.
  • CSNK2A1 variants found within ‘loop’ regions of the protein were compared with genetic variants in ‘non-loop’ regions of the protein.
  • Participants with genetic variants located within a loop region had a younger age of diagnosis, had a reported higher number of non-seizure neurological and gastrointestinal symptoms, and used more medications.
  • Participants with genetic variants located within a non-loop region were more likely to report an autism diagnosis.
  • The researchers noted that the participants with non-missense variants, such as CSNK2A1 deletions and splice site, nonsense, and frameshift variants, were more similar symptomatically to participants with variants in a non-loop region.
  • The researchers compared participants with missense variants in the Gly-rich loop to participants with all other types of missense variants. This is because the Gly-rich loop is important for CK2α’s ability to bind to CK2β, and an activating molecule called ATP. Participants with missense variants in the Gly-rich loop had a higher number of symptoms reported and an earlier age of diagnosis.
  • These findings, although limited by the number of study participants, are a first step in understanding whether variant location within the gene can affect symptom type, severity, and potential treatment strategies.Show Less
Front Hum Neurosci 19, 1589897 (2025)
Bagatelas et al.
Full Article

CSNK2A1
2025

Development and adaptive function in individuals with SCN2A-related disorders
  • The researchers aimed to describe the developmental and functional abilities of participants with SCN2A-related disorders based on different clinical groupings.Show More
  • The researchers studied 100 participants and assigned them to one of three groups: early onset SCN2A-related disorder, late onset SCN2A-related disorder, or a copy number variant (CNV) group that included SCN2A.
  • The early onset group (44 participants) was defined as having seizures that developed before 3 months old or developed between 3 months and 24 months (excluding a seizure type called epileptic spasms).
  • The late onset group (48 participants) included people who did not qualify for the early onset group.
  • The CNV group included 8 participants.
  • The researchers did not use variant function (loss of function or gain of function) to categorize SCN2A variants because not all variants have been functionally tested. But, they noted that for the variants that have been functionally tested, the participants with a gain of function variant were most often classified as early onset, and all participants in the early onset group had missense variants. Participants classified in the late onset group usually had variants that were considered to be loss of function. Of note, two participants with variants characterized as loss of function had seizures at birth.
  • Caregivers completed a comprehensive medical questionnaire and a medical interview either in-person or through a video call. Some caregivers provided additional medical records and completed a 1-year, follow-up medical questionnaire. The researchers also examined data from the Vineland Adaptive Behavior Scales-3 survey completed by Simons Searchlight participants.
  • Most participants (91 out of 100) had developmental delay and or intellectual disability, and 23 out of 80 participants over the age of 2 had an autism diagnosis, with a higher rate of people in the late onset group having autism.
  • Within the early onset group, the researchers observed three distinct phenotype sub-groups. 1) Early onset benign – self-limited infantile epilepsy that typically resolved by the age of 2, with no neurological symptoms after 2 years old. 2) Early onset intermediate – people with ongoing symptoms after 2 years, with one or more of the following: seizures, movement disorder, developmental delay/intellectual disability of up to moderate severity. 3) Early onset severe – people with severe to profound developmental impairments.
  • All participants in the early onset benign group attained their developmental milestones, whereas participants in the early onset intermediate group were often able to walk and run, but higher level skills were less often acquired, and participants in the early onset severe group had delays across all domains. Adaptive behavior scores followed a similar pattern – scores were highest (in the normal range) in the benign group, in a lower range in the intermediate group, and lowest in the severe group.
  • For the late onset group, people with seizures were less likely to be able to walk independently, and when studying this group, the researchers compared: 1) those without epilepsy, 2) those with late-onset epilepsy in childhood, and 3) those with late-onset epilepsy in mid-infancy.
  • Participants in the late onset group were more likely to experience a plateau or regression in development. This was less pronounced for participants without epilepsy. The presence of seizures had the highest association with the onset of a plateau or regression.
  • Many participants in the late onset group were able to sit and walk, and about 1 out of 5 were able to speak or follow 2-part commands. Most people without epilepsy were able to follow single commands. Adaptive behavior composite scores were similar among people in the late onset group (in the lower range), but scores were highest for participants without epilepsy.
  • This research will directly benefit families because it provides prognostic information in the absence of variant functional information. This research may also inform clinical care or the design of clinical studies.Show Less
Neurology 105, e213868 (2025)
Goad et al.
Full Article

SCN2A
2025