Copy-number variants in the contactin-5 gene are a potential risk factor for autism spectrum disorder
Bibliographic record
Abstract
Abstract BackgroundContactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD), yet previous attempts to associate copy-number variants (CNVs) encompassing CNTN5 with ASD-susceptibility were limited by insufficient statistical power. Here, we aim to clarify the putative association between CNTN5 CNVs and ASD-risk using large samples. MethodsFirst, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the findings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical profile of CNTN5 CNV carriers in the DECIPHER database.ResultsThe prevalence of CNTN5 exonic deletions and duplications was stable across ASD and across unselected cohorts (0.042% and 0.020%, respectively). We found a significant enrichment of intronic CNTN5 deletions CNVs in ASD compared to unselected controls (0.175% and 0.004%, respectively). CNVs in most cases with ASD (29 out of 30, 96.7%) were inherited. Parents transmitted the variants to their affected and unaffected children with the same frequency. No differences in exonic CNTN5 CNVs enrichment between cases with ASD compared to individuals with NDDs was observed. LimitationsThe lack of phenotypic data available for unaffected family members of probands with ASD limits the potential to assess whether CNTN5 CNVs segregate with other neuropsychiatric or sub-threshold autistic traits. Different genotyping or sequencing technologies may affect the differences in CNTN5 CNV prevalence across cohorts.ConclusionCNTN5 CNVs are rare inherited ASD susceptibility variants. They may also confer risk for other neuropsychiatric disorders. We offer a powerful framework to investigate candidate susceptibility variants that may not be detected through small-scale approaches. This approach may reveal more intermediate effect-size variants that are implicated in the etiology of ASD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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 source (direct Gemma or distilled Codex), 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".