12330 Rare Variants in SEMA3A in Individuals with Constitutional Delay of Puberty (CDP)
Bibliographic record
Abstract
Abstract Disclosure: W. He: None. E.C. Schafer: None. R. Brauner: None. A. Delaney: None. L. Dunkel: None. R. Grinspon: None. J.E. Hall: None. J.N. Hirschhorn: None. S. Howard: None. A. Latronico: None. A.A. Jorge: None. K. McElreavey: None. V. Mericq: None. P.M. Merino: None. M.R. Palmert: None. R.A. Rey: None. R.C. Rezende: None. S.B. Seminara: None. N. Shaw: None. T. Delayed Puberty Genetics Consortium: None. Y. Chan: None. Background: Constitutional delay of puberty (CDP), also known as self-limited delayed puberty, refers to late onset of puberty with relatively normal progression afterward. In contrast, idiopathic hypogonadotropic hypogonadism (IHH) results in a long-lasting defect in reproductive endocrine activity. Both CDP and IHH are highly heritable and are sometimes observed in different family members in the same pedigree. Previous work by our group and others has suggested genetic overlap between the two conditions. In this study, we aimed to identify specific IHH-related genes that are also genetic causes of CDP. Methods: The Delayed Puberty Consortium assembled exome data for 233 individuals of diverse ancestries with CDP, with onset of puberty between 12 and 18 y in girls and between 13.5 and 18 y in boys. For control data, we used exome sequencing data from gnomAD v2.1.1 (n=125,748). After data harmonization and quality control, we used a modification of the “TRAPD” method to perform gene-based burden testing for 63 genes associated with IHH. We analyzed rare variants (minor allele frequency < 0.01) with high impact (premature stop, frameshift, start-lost, stop-lost) in all individuals across ancestries (n=233), as allele frequencies for high-impact variants are unlikely to vary widely across populations. We also analyzed rare variants with moderate impact (missense, inframe insertions/deletions) predicted to be deleterious by the Primate AI algorithm (score >0.6) in non-Finnish European (NFE) individuals with CDP (n=99), then meta-analyzed the results for high- and moderate-impact variants. We considered p-values < 7.9 x 10-4 (0.05 with Bonferroni adjustment for 63 genes) significant. Results: Of the 63 genes analyzed, SEMA3A (which encodes semaphorin-3A) exhibited significant enrichment for moderate-impact variants in the NFE CDP cohort compared to controls (variant frequency in CDP vs control: 0.064 vs 0.0076, p = 1.3 x 10-4) and in the meta-analysis of both high- and moderate-impact variants (p = 3.5 x 10-6). Novel SEMA3A variants identified exclusively in CDP individuals but not in controls were a frameshift variant, p.F546fsX2, and a missense variant, I252R. Also, three missense variants in SEMA3A were observed at a higher frequency in NFE CDP individuals compared with controls: p.R66T, p.V461A, and p.T717I. No other IHH genes showed significant enrichment of rare variants in the CDP cohort. Conclusion: Rare variants in SEMA3A contribute to both CDP and IHH. While functional studies are required to assess the effects of these specific variants on protein function, previous in vitro studies of similar SEMA3A variants demonstrated defects in secretion or signaling activity. Subsequent studies employing individual-level ancestry-matched controls and larger CDP cohorts are planned to identify additional genes that contribute to CDP. Presentation: 6/1/2024
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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 | 0.000 |
| 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".