Bi-allelic PRMT9 loss-of-function variants cause a syndromic form of intellectual disability
Bibliographic record
Abstract
Protein arginine methyltransferase 9 (PRMT9) is part of the PRMT family, and it is suspected to function in pathways relevant to neurodevelopment. It is thought to participate in alternative splicing through interactions with the splicing factor SF3B2 (SAP145). In this study, we report 26 families (35 individuals) with bi-allelic loss-of-function variants in PRMT9, implicating PRMT9 in an autosomal-recessive human disease. Individuals primarily present with a neurodevelopmental disorder characterized by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia. The mutation spectrum includes 26 different variants such as frameshifting indels, nonsense variants, missense variants, and two copy-number variants. Mapping of the disease-causing missense variants onto the crystal structure of PRMT9 revealed that several of the variants reside within the catalytically active module of PRMT9, likely impairing its methyltransferase activity and resulting in a loss of function. In skin fibroblasts derived from affected individuals, we observed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Moreover, transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals. Altogether, our findings implicate bi-allelic PRMT9 loss-of-function variants as causal for neurodevelopmental disorders.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".