Rare splice and missense variants with evidence of pathogenicity in consanguineous families with autosomal recessive intellectual disability from Pakistan
Bibliographic record
Abstract
Abstract Intellectual disability (ID) is a neurodevelopmental disorder affecting up to 1-3% of people worldwide. Genetic factors, including rare de novo or rare homozygous mutations, explain many cases of autosomal dominant or recessive forms of ID. ID is clinically and genetically heterogeneous, with hundreds of genes associated with it. In this study, we performed high-depth whole-genome sequencing of twenty individuals from five consanguineous families from Pakistan, with nine individuals affected by mild or severe ID. We identified one splice and five missense rare variants (at allele frequencies below 0.001%) in a homozygous state in the affected individuals with supporting and moderate evidence of pathogenicity based on guidance from the American College of Medical Genetics and Genomics. These six variants mapped to different genes ( SRD5A3 , RDH11 , RTF2 , PCDHA2 , ADAMTS17 , and TRPC3 ), and only SRD5A3 had previously been known to cause ID. The p.Tyr169Cys mutation inside SRD5A3 was predicted to be deleterious and affect protein structure by multiple in silico tools. In addition, we found one missense mutation, p.Pro1505Ser, inside UNC13B with conflicting evidence of pathogenic and benign effects. Further functional studies are required to confirm the pathogenicity of these variants and understand their role in ID. Our findings provide additional needed information for interpreting rare variants in the genetic testing of ID.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.003 | 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".