Whole Blood Multi‐<scp>OMIC</scp> Analysis Is Effective in Clinical Interpretation of Splicing Aberrations in <scp><i>PLOD1</i></scp>‐Related Kyphoscoliotic Ehlers‐Danlos Syndrome
Bibliographic record
Abstract
Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) Type 1 is a rare hereditary connective tissue disorder due to biallelic deleterious variants in PLOD1 and is mainly characterized by hypotonia, congenital kyphoscoliosis, eye fragility, hyperextensible skin, Marfanoid habitus, and joint hypermobility. In PLOD1-kEDS, deleterious variants are typically loss-of-function alleles. Therefore, the identification of private non-canonical splicing variants might deserve functional studies to refine their clinical interpretation. In a 7-year-old boy with congenital hypotonia, kyphoscoliosis, joint hypermobility, and arachnodactyly, exome sequencing revealed the homozygous variant c.1756-13C > A in PLOD1. This variant was previously annotated in public databases with conflicting pathogenicity criteria. In contrast to other EDS subtypes whose causative gene is not expressed in peripheral lymphocytes, whole blood RNA sequencing demonstrated a deleterious effect of the identified variant, which resulted in the incorporation of 11 intronic nucleotides and the generation of a premature stop codon. In this work, multi-OMIC analysis on peripheral blood was a rapid and reliable tool to clinically characterize a non-canonical splice site variant in PLOD1-kEDS.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.003 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".