Identification of Two Rare Homozygote Missense Variants in the <i>IRS1</i> Gene in a Patient With Early Gestational Diabetes: A Case Study
Bibliographic record
Abstract
Background: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and has a rising prevalence worldwide. Environmental and genetic factors contribute to GDM risk. Describing familial cases of GDM can help identify the disease's genetic components. Methods: Here, we report the case of an Emirati female patient affected with early GDM and familial history of diabetes with a significant level of insulin resistance. As a first step, we investigated the GCK and HNF1A gene sequences by direct sequencing and then performed a clinical exome sequencing (CES) of the patient's genomic DNA covering 6,670 genes. Results: Our findings showed the absence of any pathogenic variants in the GCK and HNF1A gene sequences. In addition, the CES excluded all maturity-onset diabetes of the young (MODY)-related genes. However, two rare homozygous variants in the insulin receptor substrate 1 ( IRS1 ) gene were identified: p.Pro948Leu (gnomAD minor allele frequency (MAF) = 7.5 × 10 -5 ) and p.Arg1221Cys (gnomAD MAF = 5.6 × 10 -5 ). These variants were absent in a set of healthy Emirati individuals. Both variants are highly conserved among mammalians but have never previously been reported among the same haplotype or individual. p.Pro948Leu and p.Arg1221Cys are localized close to two important functional phosphorylation sites recognized by PI3K (hTyr941) and SHP2 (hTyr1229), respectively. Moreover, the independent and combined effect of the two variants on protein stability was predicted to be destabilizing. Conclusion: Our investigation emphasized the role of downstream regulators of insulin signaling in GDM pathophysiology and identified IRS1 as a candidate gene to explain chronic insulin resistance. In addition, the patient showed significant health improvement after lifestyle modifications and oral antidiabetic administration, even after withdrawing insulin injections. J Endocrinol Metab. 2022;12(6):188-197 doi: https://doi.org/10.14740/jem842
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.004 | 0.002 |
| 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".