Biallelic Mutations in <i>P4HTM</i> Cause Syndromic Obesity
Bibliographic record
Abstract
We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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) | 0.002 | 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".