Identification of MC4R and VCP Genetic Variants in Two Pakistani Families Showing Symptoms of Diabetes, Hyperphagia, Seizures, and Obesity
Bibliographic record
Abstract
Variations in the melanocortin 4 receptor (MC4R) are most commonly associated with serious early-stage monogenic obesity. The valosin-containing protein (VCP) gene, also referred to as p97, produces the ubiquitous, crucial, and multifunctional protein VCP, involved in a wide range of cellular processes, including endoplasmic reticulum-associated degradation (ERAD), degradation of lysosomal protein, and degradation of the proteasome-mediated protein. In the present study, we investigated two Pakistani families enrolled from Sibi, Pakistan, for variation in MC4R and VCP genes. Clinical symptoms involved obesity, hyperphagia, and diabetes in Family 1. Obesity with autism spectrum disorder (ASD), hyperphagia, diabetes, seizure, gastrointestinal, and sleep disorders were found in Family 2. Additionally, blood samples were collected and DNA extraction was performed. Subsequent molecular analysis was conducted to identify mutations. Clinical and genetic results were analyzed, and the segregation of MC4R and VCP gene variants in the families helped to make the diagnosis of the disease. For the identification of variations, we conducted whole exome sequencing (WES) and confirmed the findings through target sequencing. We divulged two previously reported heterozygous missense variations. Notably, WES revealed variants (c.307G>A, rs2229616) in the MC4R and (c.1360-35A>G, rs2258240) in the VCP genes in both families separately. The chromatogram illustrated homozygous unaffected siblings and parents, as well as heterozygous individuals with the disease. Both families segregate with the obesity disorder in an autosomal dominant manner. In Family 1, the change from ‘G’ to ‘A’ in the MC4R gene depicts the mutant allele ‘A’ segregating dominantly from one generation to another. Similarly, the change from ‘A’ to ‘G’ in the VCP gene illustrates the mutant allele ‘G’ segregating dominantly in Family 2.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".