BackgroundPPP1R3F deficiency syndrome is an extremely rare, recently identified X-linked recessive neurodevelopmental disorder. It is caused by hemizygous variants in the PPP1R3F gene, which encodes a glycogen-targeting subunit of the brain-specific protein phosphatase 1 (PP1). Dysfunction of PPP1R3F disrupts glycogen metabolism in astrocytes, leading to insufficient energy supply to synapses during critical periods of brain development and subsequently causing neurodevelopmental abnormalities. Only a small number of cases of PPP1R3F deficiency syndrome have been reported to date, which significantly limits our comprehensive understanding of the clinical features of the disease and the relationship between genetic variants and clinical manifestations in patients.MethodsWhole-exome sequencing (WES) was performed on a Chinese male presenting with intellectual disability (ID), developmental delay (DD), and autism spectrum disorder (ASD). Sanger sequencing was then used to identify and determine the origins of the variant. We evaluated the pathogenicity of the identified variant following the established ACMG/AMP guidelines. Additionally, we conducted a thorough review of previously reported cases to summarize the variants and clinical features of PPP1R3F deficiency syndrome.ResultsWe identified a novel hemizygous nonsense variant [NM_033215.5: c.907C>T, p.(Gln303*)] in the PPP1R3F gene in the proband, which was inherited from his mother. The patient we described here exhibited clinical phenotypes similar to those associated with PPP1R3F gene variants but lacked other reported multisystem manifestations, such as epilepsy, brain abnormalities, and dysmorphic features. An analysis of the 15 variants and their associated phenotypes in 15 patients from both the current and previous studies demonstrates that PPP1R3F gene variants can lead to a variety of phenotypic deficits, and a clear genotype–phenotype correlation has not yet been established. Despite the high variability in some clinical manifestations, the core phenotypic features of PPP1R3F variants include varying degrees of ID, DD, speech delay, dysmorphic facial features, and ASD.ConclusionOur findings support DD, ID, ASD, and speech impairment as core features of PPP1R3F deficiency syndrome, while also highlighting the extensive clinical variability. This study further expanded the genetic and phenotypic spectrum associated with PPP1R3F deficiency syndrome.
Brain Quality Control Selectively Eliminates Neurons with Abnormal Variants in Development
By analyzing genomic data from neurons, scientists from Harvard Medical School (HMS), Boston Children’s Hospital, and their collaborators have gained insights into a critical quality-control mechanism that takes place in the developing fetal brain.
During development, the human brain generates an excess of neurons, most of which are eliminated around when the baby is born. According to a study published this week in Nature, scientists report that neurons with multiple copy number variants, including DNA duplications or deletions, are widespread in the developing brain. However they are selectively eliminated shortly before or after birth likely because the genomic alterations disrupt their ability to form synapses.
Full details are provided in a paper titled “Perinatal elimination of genetically aberrant human cortical neuron.” The findings reported there are significant because copy number variants can impact brain function and may contribute to neuropsychiatric conditions, including autism, schizophrenia, epilepsy, and intellectual disability. A better understanding of the pruning process in the developing brain could improve how autism and other disorders in which neural development goes awry are treated.
As Diane Shao, MD, PhD, HMS instructor of neurology at Boston Children’s and a co-first author on the study noted, “If that quality control system can be disrupted, that could be part of what goes wrong in neurodevelopmental disorders like autism. Understanding the mechanism could eventually point us toward what to look for, and maybe what to protect.”
One of the first steps in the study was exploring the prevalence of copy number variants in developing human brains. To do that, the scientists designed single-cell whole genome sequencing approaches that allowed them to lightly sequence the genomes of single neurons. They used this method to sequence over 1,500 neurons from 16 individuals. They then validated the results with deeper sequencing of over 800 neurons from 12 individuals. They then used various computational methods to identify copy number variants in each sequenced genome. With their approach, it was possible to see the genomic changes “one neuron at a time, map where in the genome they occur, and compare how common they are from before birth to old age,” explained Peter Park, PhD, co-senior author on the paper and professor of biomedical informatics at HMS.
The data showed that an average of nearly 26 percent of neurons in the prenatal cortex had widespread copy number variants, but this rapidly decreased to an average of 6.2 percent after birth. Specifically, “neurons with widespread CNVs were mainly eliminated perinatally, timed roughly parallel to periods of programmed cell death, whereas neurons with smaller CNV burdens declined slowly in frequency with postnatal age,” the scientists wrote.
“We were totally unprepared for how common these were in early development,” said Christopher Walsh, MD, PhD, a co-senior author on the paper and professor of pediatrics and neurology at Boston Children’s Hospital. “But it makes sense in the context of what we know about the formation of excess neurons and in the context of the IVF literature.”
Next, the team explored the pathways through which the abnormal neurons are eliminated. By sequencing and analyzing DNA and RNA from over 44,000 individual cells, they found that neurons with widespread copy number variants also had abnormal expression of the genes involved in the creation and maintenance of neural synapses. It suggests that unlike healthy brain cells, these abnormal neurons fail to make critical connections during fetal development which causes them to die off.
“This competition for synapses has been described for years, but without the benefit of a genomic understanding,” Walsh noted. We didn’t realize that this struggle for survival—this Darwinian competition—was nature’s quality control mechanism in the brain.”
As part of the study, the team also confirmed some earlier findings that flawed neurons continue to be eliminated throughout adulthood, albeit at a much slower rate. Currently, they are looking into whether this neural elimination process is different in developing brains of people with autism and other neurodevelopmental disorders. They are also exploring whether this process plays a role in development of adult-onset neurodegenerative disorders like Alzheimer’s disease.
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The BELONG Study: Black Equality in OCD NeuroGenomics
By Boris Litvin, MA, Matthew Riello, Andrew Marshall, PhD, Emily Rodriguez, MS, MSc, Martha Falkenstein, PhD, and Alexander Rosenberg
One word appears more and more in the news surrounding mental health research (and the IOCDF Newsletter and blog): “genomics”. What does it mean, and why is it such a hot topic lately for both scientists and non-scientists? In the context of OCD research, genomics refers to the study of a person’s genome (all of a person’s genes) to gain insight into how OCD appears and develops.
Genomic studies of OCD over the past two decades have contributed significantly to our understanding of how OCD works. However, there remains more to be done and explored, for OCD as well as for other psychiatric conditions.
With support from a five-year grant by the National Institutes of Health (NIH), researchers at the Mount Sinai School of Medicine (New York, NY), Baylor College of Medicine (Houston, TX) and University of North Carolina at Chapel Hill (UNC) (Chapel Hill, NC) have launched the Black Equality in OCD NeuroGenomics (BELONG) study, a research project that looks specifically at the genomes of Black and African Americans with OCD and their families. BELONG aims to contribute to OCD research from multiple perspectives: first, enhancing our overall understanding of OCD genomics, second, achieving a deeper grasp of OCD risk by adding more participants, and, third, gaining more reliable insight into OCD risk by leveraging the power of human diversity.
For the first point, the lead investigator of the BELONG study, together with Dr. Sidney Hankerson, Mount Sinai’s Dorothy Grice, MD, explained: “We know that there are gene variants that significantly increase risk for OCD. When are those genes active developmentally? Can we understand more about where those gene products function in the brain? What part of the brain? What works in partnership with that part of the brain in terms of brain circuitry?”
For the second, Grice added, “Progress in OCD research has been limited by smaller sample sizes compared to other psychiatric conditions, for example, in 2018, there were samples from 130,000 individuals with major depression, about 60,000 individuals with schizophrenia and 20,000 individuals with bipolar disorder and fewer than 3,000 samples from individuals with OCD. These numbers have grown significantly since 2018, but OCD continues to be underrepresented in genetic research. Increasing the sample sizes has tremendous potential to advance our understanding of OCD genetics.”
Third, according to Grice, much of OCD research has mostly involved individuals with European ancestry: “Thinking about OCD and Black Americans, the prevalence is not any different. So it’s not because it doesn’t happen in other cohorts or populations — it’s because those individuals are not being included or not participating for a variety of reasons. So one motivation for our study is to try to get studies in OCD to reflect the real world and the population that’s out there.” Dr. Grice added, “This is a powerful tool to understand the genomics of OCD across all of human ancestry.”
Dorothy Grice, MD (Mt. Sinai School of Medicine)
James Crowley, PhD (University of North Carolina, Chapel Hill)
Bridging Gaps
The number of people participating in OCD genomic studies has grown significantly over the past ten years, which was partly due to the emergence of the international Psychiatric Genomics Consortium (PGC) in 2007. However, the lack of diversity persisted, even for research published by PGC scientists. “This past year, the largest genomewide association study ever was published, with over 53,000 individuals with OCD (Strom et al., 2025),” said Baylor’s Eric Storch, PhD. “Despite all its strengths, virtually no one within the sample was of any sort of racial or ethnic diversity. When you start modeling effects of genetic composition on things like predicting treatment response, it doesn’t represent the beautiful diversity of our world.” Storch continued, “With such a lack, that really has a risk of creating a health disparity where many individuals that comprise our world would not be represented, or not benefit from those discoveries.”
“Humans came out of Africa,” noted UNC’s James Crowley, PhD. “If all of our genetic diversity goes back to Africa, and you focus just on individuals of European ancestry, you are only looking at a fraction of all the genetic diversity on the planet. There have been a lot of initiatives to include genetic data from individuals of African ancestry, and they have not been as successful as we would like. There are systemic barriers to access to assessment, treatment and biomedical research. We have an opportunity in this study to advance biomedical research in the African American community.”
Grice noted that, for Black Americans, “There’s a lot of hesitancy to participate in research studies, given the tragic history in that regard. In addition, we know that there’s a much higher rate of misdiagnosis in Black Americans. People may present with what may be OCD, but there are higher rates of being misdiagnosed as having anxiety or psychosis, even to the point of being inappropriately hospitalized compared to other groups.”
The BELONG team is hopeful that their efforts will contribute to the comparatively small amount of research on OCD in Black Americans. Baylor’s Ogechi “Cynthia” Onyeka, PhD, remarked, “With regards to understanding symptom presentation and expression, the literature on what OCD looks like in the Black community is very limited and restricted to a group of papers that were written 10-15 years ago. We are really excited to pick up where that limited literature has left off and not only understand what some of the symptom dimensions are that might be more prevalent, but also build upon that and get more information out to individuals who might think they have OCD to help support treatment awareness and engagement too.”
Eric Storch, PhD (Baylor College of Medicine)
Ogechi “Cynthia” Onyeka, PhD (Baylor College of Medicine)
How BELONG Contributes to Science
How would genomics research contribute to knowledge of OCD, and further advances in treatment? Grice explained, “We’re focusing on rare genetic variation, and particularly de novo variation— which indicates a new, spontaneous genetic change that occurs randomly very early in embryonic development.”
To understand the role of de novo variation, BELONG invites not only Black Americans with OCD to participate, but also their family members, with a goal of at least 1,250 participants by the end of the study. The process for participating in BELONG is fairly simple, and anyone in the US can take part. Storch explained, “Go to our website (https://belongocd.com/), or email one of us. From there it’s a simple interview and mailing us a saliva sample via a kit that we provide. We also provide some compensation to participants for their time and effort.”
Naturally, concerns about the safety of DNA collection and storage can arise. “There’s a lot of oversight and attention to ensure our study is compliant with all the current ethical and confidentiality rules that are in place on every level,” Grice said. Crowley added, “First: there’s no for-profit institution involved in any of this research. Second: we remove all identifiers, like name, birthplace, and date of birth. All of that information is stripped from any of the genetic data. Third: the way that we work with the data is very controlled and regulated by each institution’s ethical review board.”
Importantly, this security extends to research conducted by future researchers who may access the data for years to come. The BELONG team adheres to strict federal and institutional standards to promote the safety of participants. Like many studies funded by the NIH, BELONG data will be available for future research. “With the consent of each participant, we share their anonymous information with NIH because NIH has a data repository available to other vetted and qualified researchers who can extend our work,” Grice specified. “The participants are doing so much for our study and if a researcher comes along in ten years with a great new idea that can benefit the field, they can apply to use this information. Every participant in BELONG is advancing knowledge of OCD today and in the future. And that’s fantastic.”
It all comes back to the participants. “We try to answer questions, make sure people feel comfortable about participating — that’s all a part of the informed consent process, to make sure that all the questions are answered about why we’re doing this study, what the study entails and how the participants are protected, before they actually get into the study. We want people to understand what it’s all about and make sure they have the knowledge that they need to make an informed decision about whether they want to join or not,” said Grice.
Beyond BELONG
While the BELONG study highlights and addresses major gaps in both genomics and OCD research, it is important to be mindful that all research has limitations, especially with the interpretation and extrapolation of data. Fellow scientists and clinicians like Sonya Faber, PhD, at the University of Ottawa warned that the results of genetic research could be misconstrued to “reinforce scientific racism and biological determinism, rather than addressing the structural and psychosocial contributors to mental health disparities.” Faber also noted that racially-based genetic studies could “risk excluding or misclassifying participants of mixed ancestry—who often face the same structural barriers but may be excluded for not fitting a clean racial “genetic” category”. Grice notes that African Americans are overwhelmingly of mixed ancestry and hence the BELONG study is in a unique position to address these risks. Similarly, Emory University School of Medicine’s Donovan Ellis, PhD, expressed, “[We want] to be mindful that we’re not reifying race science-based conclusions, or coming to the types of conclusions that unintentionally further marginalize communities, or be overly narrow”.
Both Faber and Ellis asserted that genetic risk factors for psychological disorders are not tied to race. Citing genetic research into schizophrenia, Faber explained, “Although there are now genes associated with the risk of developing schizophrenia, these do not directly correspond to higher risk by race, as race is a sociopolitical and not a genetic classification” (Faber et al., 2023). “This logic applies equally to OCD,” she stated.
Emory University clinical psychologist Joya Hampton-Anderson, PhD, suggested that this important study should ensure to carefully consider the cultural context and historical stigma associated with medical research and minority groups: “I think the alignment with the community is going to be really important with something like saliva samples being taken. There is a lot of historical mistrust in the Black community around medicine, broadly defined, but also research, and that is a very intimate data collection method.”
With these concerns in mind, Faber described how epigenetic factors may play a role in linking genetics with OCD. Epigenetics refers to how one’s behavior or environment can impact and interact with their own genome. “Since belonging to a certain race corresponds to an environmental risk of poor mental health (i.e., social disadvantage)…an association between race and [mental disorders] may be expected to be observed,” said Faber; these risks may include “chronic exposure to racism, discrimination-related stress, intergenerational trauma, and environmental adversity (housing, pollution, policing, poverty)”. Faber continued, “Epigenetics provides a far more accurate and justice-consistent framework for understanding why racially minoritized groups may show different biological profiles—without invoking race as a proxy for genetic difference”.
Faber concluded citing Bryant et al. (2022): “While ethnicity allows individuals the agency to self-define through shared culture and ancestry, race is an artificial category externally imposed to rank and divide human variation. Decades of genetic data confirm that race is not a proxy for genetics, but rather a proxy for the impacts of structural racism”.
Advancing OCD Research, One Saliva Sample at a Time
The BELONG researchers have acknowledged these concerns head-on. Regarding potentially reinforcing biological determinism, Grice explained, “We’re not thinking there will be different genes involved compared to other ancestries, but given all the ancestral population changes and genetics, there probably will be different genetic variants within a particular gene, which will help us to learn more about the biology of OCD, because not all genetic variation actually leads to a problem”. In fact, Grice notes that other ongoing psychiatric genetic studies in autism and schizophrenia that also focus on rare de novo variation do not show evidence for different biological profiles across different ancestries, so there is good reason to think these issues will be moot in BELONG.
Grice also clarified: “This study is focusing on genetics which plays a very important role in risk for OCD, and while there are also important non-genetic or environmental factors, those are not a focus of this particular study. We’re not saying it’s all genetic, but that is what we’re focusing on in BELONG”.
Recognizing the complex history of medical research involving minority communities, Onyeka reiterated that “We have a community advisory board that we’ve been working with, with different clinicians who are Black who work within this space in terms of providing treatment and therapy, and getting feedback from folks who are on the ground and actually engaging with these patients has also been helpful too”.
Despite genetics being the focus of the study, Onyeka mentioned that working directly with minority communities can provide insight into the environmental factors that shape OCD “I think one thing that I’m really excited about is the phenotypic component of this study. In addition to getting a really good assessment of OCD with the participants, we’re also getting a lot of different perspectives about different socioecological factors that might be related to OCD. Things like ethnic identity membership and awareness of treatment of symptoms and other things that, with a large sample, we hope to obtain”.
Jordan Cattie, PhD, of Emory University School of Medicine expressed, “Researchers can build trust by using approachable, clear, and informative language about how a study can help, or is different from previous work. For example, this study team shared that (in both existing genetics and OCD treatment studies) there is significant underrepresentation of Black Americans, which makes representation a really important priority. This study team is unique in including a community advisory board that focuses on how to make research helpful for communities, as well as health equity researchers.”
Many researchers and clinicians remain hopeful about the prospects of this research and understand its importance in expanding the knowledge of OCD risk.
“Ultimately, BELONG represents a unique research study that goes beyond the laboratory. This research is really grounded in altruism,” said Onyeka. “It’s a one-time experience for the participant — to be able to meet for the assessment, get an understanding of what OCD looks like for them, have the validation of talking to somebody about their symptoms, which can be really validating and helpful and affirming, and then participate with regards to the genetic component. But the dividends of that participation go far beyond what we can even operationalize or quantify right now, which is something that’s really incredible and not something that you see a lot with research in the Black community. I think just what makes this study really unique is how far your participation can go.”
References
Bryant, B. E., Jordan, A., & Clark, U. S. (2022). Race as a Social Construct in Psychiatry Research and Practice. JAMA psychiatry, 79(2), 93–94. https://doi.org/10.1001/jamapsychiatry.2021.2877
Faber, S. C., Khanna Roy, A., Michaels, T. I., & Williams, M. T. (2023). The weaponization of medicine: Early psychosis in the Black community and the need for racially informed mental healthcare. Frontiers in psychiatry, 14, 1098292. https://doi.org/10.3389/fpsyt.2023.1098292
Strom, N.I., Gerring, Z.F., Galimberti, M., Yu, D., Halvorsen, M.W., Abdellaoui, A., Rodriguez-Fontenla, C., Sealock, J.M., Bigdeli, T., Coleman, J.R., Mahjani, B., Thorp, J.G., Bey, K., Burton, C.L., Luykx, J.J., Zai, G., Alemany, S., Andre, C., Askland, K.D., Bäckman, J., … Mattheisen, M. (2025). Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. Nature Genetics, 57(6), 1389–1401. https://doi.org/10.1038/s41588-025-02189-z
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Increased frequency of rare damaging variants in PLIN4 in patients with anorexia nervosa
BackgroundAnorexia nervosa (AN) is a severe psychiatric disorder characterized by pathological fear of weight gain, persistent restriction of energy intake, and pervasive body image disturbance. Although AN is substantially heritable, the rare coding variants contributing to susceptibility remain incompletely defined. Pedigree-based whole-exome sequencing studies can help to identify rare, high-effect protein-coding variants and thereby elucidate disease mechanisms.MethodsWhole-exome sequencing was performed on AN-dense family pedigrees to identify candidate genes. The frequency of rare (minor allele frequency <1%), putatively damaging [combined annotation-dependent depletion (CADD) >15, including predicted loss-of-function (LOF)] variants in 32 candidate genes was assessed in 154 unrelated probands of European ancestry. Carrier counts were compared against gnomAD v4 non-Finnish European reference using a TRAPD-style coverage-adjusted denominator (maximum allele number/2 across qualifying sites per gene). Significance was assessed by one-sided Fisher exact test, Bonferroni-corrected across 32 candidate genes.ResultsPLIN4 was the only gene enriched in AN cases at Bonferroni-corrected significance: 17 of 154 patients (11.0%) carried a rare damaging variant versus 3.2% in gnomAD non-Finnish Europeans [odds ratio (OR) 3.86, 95% confidence interval (CI) 2.35 to 6.35; one-sided Fisher p = 9.98e−06; Bonferroni-corrected p = 3.19e−04]. The result is preserved with the index proband removed (n = 153; OR 3.64, 95% CI 2.18 to 6.07; corrected p = 1.13e−03). Six of 154 patients carried predicted LOF variants; 4 of 6 had at least one AN-affected first- or second-degree relative carrying the same variant, providing co-segregation evidence. The LOF-only burden did not survive Bonferroni correction in isolation.ConclusionsPatients with AN carry a statistically significant excess of rare, putatively damaging variants in PLIN4, at a threshold surviving Bonferroni correction across 32 candidate genes. These findings implicate lipid-droplet biology as a candidate contributor to AN pathophysiology.
Nicotine and tobacco smoke reshape neuronal signaling networks from a single-nucleus transcriptomic perspective
Nicotine and cigarette smoke exposure significantly impact brain function, yet their distinct cellular and molecular mechanisms remain unclear. To address this, we conducted comprehensive single-nucleus RNA sequencing (snRNA-seq) analysis on whole-brain samples and specifically on the ventral tegmental area (VTA) of adult C57BL/6 mice following nicotine or smoke exposure. Our study identified 18 major transcriptionally distinct cell populations across the whole brain and 27 distinct clusters within the VTA, covering major neuronal and glial cell types. Differential gene expression and KEGG pathway enrichment analyses revealed distinct transcriptional responses: nicotine exposure was associated with enrichment of synaptic and addiction-related transcriptional pathways in neuronal populations, including dopaminergic and glutamatergic pathways, whereas smoke exposure was associated with broader enrichment of metabolic-, immune-, and endocrine-related pathways. CellChat predicted condition-associated communication differences, including higher inferred NRXN communication from excitatory neurons to oligodendrocytes and other excitatory neurons under nicotine exposure. Smoke exposure also increased oligodendrocyte PISD expression, a transcriptomic change potentially associated with mitochondrial phospholipid metabolism. Collectively, these data define cell-type-specific transcriptional and predicted communication signatures of nicotine and smoke exposure that require functional validation.
Electronic Health Record–Based Phenotyping for Obsessive-Compulsive Disorder: Algorithm Development and Multicenter Validation Study
Background: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder, with two-thirds of affected individuals reporting severe impairment. Despite its substantial burden and moderate heritability, the etiology of OCD remains poorly understood, and treatments are often suboptimal. Although recent genome-wide association studies (GWAS) have identified some risk loci, much of the genetic architecture of OCD remains undiscovered, underscoring the need for scalable approaches to identify large, well-defined patient cohorts. Objective: This study aimed to develop and validate a scalable electronic health record (EHR)–based phenotyping algorithm for identifying OCD cases to support large-scale genetic and translational research. Methods: We leveraged EHR-linked biobank data from 2 large hospital systems, namely Vanderbilt University Medical Center (VUMC) and Mass General Brigham (MGB), to develop a high-throughput phenotyping algorithm integrating diagnostic codes, medication records, and natural language processing (NLP) of clinical notes. Algorithm performance was evaluated through expert chart review, and genetic analyses were performed in individuals of European genetic ancestry using the polygenic scores (PGS) of OCD, major depressive disorder (MDD), and height derived from the most recent GWAS. Results: Expert chart reviews demonstrated our algorithm combining both () codes and NLP achieved the highest positive predictive values (PPV) for OCD case identification (0.84 at VUMC; 0.91 at MGB) compared to using either codes or NLP alone, albeit with reduced case yield. At both sites, algorithm-defined OCD cases of European genetic ancestry showed significantly higher OCD PGS than controls. In sensitivity analyses adjusting for MDD status, OCD PGS associations were more robust than MDD PGS associations, while height PGS showed no association, supporting the genetic plausibility and relative specificity of the phenotype. Conclusions: This study presents a scalable and cost-efficient EHR-based approach for identifying OCD cases across health systems. The algorithm achieves high PPV, and among individuals of European genetic ancestry, algorithm-defined cases show significant OCD PGS enrichment, supporting its utility for large-scale genetic studies and advancing understanding of the disorder’s complex etiology.
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AI Tool Helps Link BRSK1 Variants to Neurodevelopmental Disorder
For many families affected by rare genetic conditions, genomic testing does not immediately deliver an answer. Now, researchers have combined artificial intelligence, human genetics, and fruit fly experiments to connect variants in BRSK1 with a complex neurodevelopmental disorder. The findings provide a potential diagnosis for several previously unexplained cases while offering clues about how reduced activity of the gene may disrupt nervous system development.
The study, “Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy,” was led by researchers at Baylor College of Medicine, the Duncan Neurological Research Institute at Texas Children’s Hospital, and the Texome Project, together with collaborating institutions. It was published in the American Journal of Human Genetics.
According to Hugo Bellen, PhD, who is co-lead author of the study, the work began with a child enrolled in the Texome Project, which provides genetic testing to medically underserved people with rare, undiagnosed conditions in Texas. Standard analysis of the child’s and parent’s genomes had not identified a cause. AI-MARRVEL, an artificial intelligence–based tool that analyzes genomic and clinical information to prioritize candidate disease variants, highlighted a rare change in BRSK1. Through GeneMatcher, the researchers identified nine additional affected individuals with rare heterozygous variants in the gene, bringing the group to 10 people from seven unrelated families. The team then modeled three patient-derived variants in Drosophila melanogaster to test their effects in a living organism.
The “affected individuals present with developmental delay and variable phenotypes including anxiety, attention-deficit hyperactivity disorder (ADHD), autism, and seizures,” the authors wrote, adding that the severity and symptoms varied. Symptoms differed even among relatives carrying the same variant, suggesting variable expressivity.
“We studied the fly equivalent of BRSK1, called sff (sugar-free frosting), and found that this gene is active primarily in neurons, mirroring the expression pattern seen in humans,” added Mingxi Deng, PhD, who is first author and a postdoctoral fellow in the Bellen lab. “When the fly gene was disabled, the flies developed difficulties moving, showed increased sensitivity to stressors that can trigger seizure-like behavior, became more vulnerable to heat-induced paralysis and lived shorter lives. These findings indicated that the gene is essential for normal nervous system function.”
Introducing normal human BRSK1 largely corrected the behavioral and neurological defects, whereas three variants (BRSK1p.Ile202Val, BRSK1p.Arg237Cys, and BRSK1p.Thr406Ile) found in affected individuals produced only a partial rescue. The patient variants also failed to normalize neuromuscular junction structure or levels of Futsch, a protein involved in organizing neuronal microtubules. Together, the experiments suggest that the variants partially reduce BRSK1 activity rather than eliminating it.
“Microtubule disruption has been linked to several neurodevelopmental and neurological disorders,” Deng said. “Our findings suggest that reduced BRSK1 function interferes with the cellular machinery needed for healthy brain development and communication between neurons.”
BRSK1 encodes a kinase involved in neuronal polarization, synaptic function, and the internal organization of nerve cells. Reduced activity may therefore interfere with the cellular machinery neurons need to develop and communicate. “This work improves our understanding of the genetic causes of neurodevelopmental disorders and highlights the power of combining AI-driven gene discovery with experimental studies in model organisms to uncover new rare diseases and their underlying biology,” Bellen said.
The diagnosis may help participating families understand the source of their condition and could guide recognition of additional cases. Future studies will be needed to determine why the same variant can produce markedly different symptoms and to define more precisely how altered BRSK1 activity affects the developing brain.
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The chain-mediating effect of societal pressure on appearance and body image on fear of negative evaluation and social anxiety in women with polycystic ovary syndrome: a cross-lagged panel analysis
Objective(Prospective Longitudinal Observational Study) This study aimed to examine the longitudinal chain mediating roles of physical appearance social pressure and body image in the relationship between fear of negative evaluation (FNE) and social anxiety among women with polycystic ovary syndrome (PCOS), and to clarify the temporal sequencing among these variables.MethodsConvenience sampling was used to recruit 264 women with PCOS. Participants completed the Sociocultural Attitudes Towards Appearance Questionnaire-4 Revised (SATAQ-4R), Body Image States Scale (BISS), Brief Fear of Negative Evaluation Scale (BFNE), and Social Anxiety Scale (SAS) at baseline (T0), 3 months (T1), and 6 months (T2), yielding 242 valid cases. Data were analyzed using measurement invariance testing, cross-lagged panel analysis (CLPA), and bootstrapping.ResultsFull measurement invariance was established across the three timepoints (ΔCFI ≤0.01, ΔTLI ≤0.01). The final CLPA model demonstrated excellent fit (CFI = 0.988, TLI = 0.959, RMSEA = 0.023, 90% CI: 0.021–0.026). T0 FNE positively predicted T1 appearance social pressure (β = 0.25, P <0.001) and T1 SA (β = 0.23, P <0.001), and negatively predicted T1 body image (β = −0.19, P <0.001). T1 appearance social pressure positively predicted T2 SA (β = 0.22, P <0.001). T1 body image negatively predicted T2 SA (β = −0.18, P <0.01). T1 SA positively predicted T2 FNE (β = 0.13, P <0.001). Bootstrap analyses revealed significant indirect effects via T1 appearance social pressure (β = 0.055, 95% CI: 0.028–0.082) and T1 body image (β = 0.034, 95% CI: 0.015–0.053), as well as a significant chain mediation effect (β = 0.018, 95% CI: 0.007–0.029).ConclusionLongitudinal evidence supports a chain mediating pathway wherein elevated fear of negative evaluation at baseline is prospectively associated with subsequent increases in appearance social pressure and declines in body image, which in turn correspond to higher levels of social anxiety in women with PCOS. Findings support the potential utility of early psychological screening and targeted interventions addressing maladaptive cognitions and body image disturbances, although causal efficacy requires validation via randomized controlled trials.
Body-based therapies and transcranial magnetic stimulation for posttraumatic stress disorder: a proposed integrative approach
Posttraumatic stress disorder (PTSD) remains difficult to treat, with 30–50% of patients retaining their diagnosis after first-line trauma-focused psychotherapies. Body-based therapies (BBTs) and transcranial magnetic stimulation (TMS) have each shown preliminary benefit for PTSD but have not yet been studied in combination. To our knowledge, this is the first proposal to integrate these modalities as a combined therapeutic approach. PTSD involves disrupted coordination across multiple levels of neural organization, from cortical regulatory networks to limbic threat circuits and autonomic systems. BBTs are theorized to engage bottom-up processes, including autonomic regulation and interoceptive recalibration, while TMS operates through top-down modulation of prefrontal-limbic circuitry and large-scale network connectivity. This complementarity suggests that a combined approach could engage a broader range of PTSD-related dysfunction than either intervention alone. This article reviews the evidence and proposed mechanisms for each modality, places both within current models of PTSD neurocircuitry, and examines potential pathways of interaction including neuroplasticity priming and autonomic stabilization. Important risks are also addressed, including autonomic destabilization, unknown optimal sequencing, and the open question of whether mechanistically distinct treatments produce additive benefits. The case for combining BBTs and TMS is presented as a hypothesis warranting further investigation.
A conceptual multi-agent architecture for mental health triage in post-conflict Arabic-speaking populations: a theoretical proposition and staged validation argument
Syria’s protracted conflict has produced a mental health crisis of extraordinary scale, with post-traumatic stress, depression, and anxiety estimated at several times global baselines, set against fewer than 0.37 psychiatrists per 100,000 people. Existing AI mental health tools have been developed and evaluated primarily for English-speaking, non-humanitarian populations, and their transfer to this setting is constrained by three simultaneous structural deficiencies—extreme clinical scarcity, Arabic natural-language-processing underperformance for dialect, and cultural misalignment with Syrian idioms of distress—which we term the Triple Gap. This article is a conceptual contribution in the Hypothesis and Theory genre, and its central claim is theoretical rather than technical: that AI-assisted mental-health triage at a safety floor adequate for crisis relevant care in this setting is conditional on the joint satisfaction of three constraints—linguistic adequacy for the local dialect, cultural validity for local idioms of distress and help-seeking, and bounded clinical responsibility through human oversight. These constraints interact, so that a system satisfying fewer than all three is expected to fail in clinically consequential rather than random ways. As one possible design response to this proposition—neither the only one nor a validated one—we describe a conceptual multi-agent architecture aligned with the WHO mhGAP task-shifting model: a four-stage pipeline (screening, risk stratification, routing, follow-up) constrained by a cross-cutting cultural-adaptation layer, augmented by candidate verification mechanisms with explicit abstention, and governed by human oversight in which clinical responsibility rests with a licensed clinician. The proposal is a hybrid clinical decision support hypothesis, not an autonomous system. Because no Syrian Arabic clinical corpus yet exists, the conversational components of the design cannot presently be evaluated; we therefore set out a staged sequencing argument for future work in which the construction of a Syrian Arabic Mental Health Evaluation Corpus (SAMHEC) is the first and rate-limiting condition. We present no prototype, no corpus, and no clinical, cultural, or safety evaluation, and we make no claim of clinical validity, safety, or readiness for deployment. The contribution is the integration of multi-agent triage with task-shifting and cultural adaptation into a single conditional argument whose adequacy can be established only through the staged empirical work we describe.